Microstructure-based wound closure devices

ABSTRACT

The present invention relates generally to wound closure device comprising one or more microstructures. The devices are designed such that the microstructures are able to grip the skin or tissue surrounding a wound, optionally closing the wound, or securing the tissue or skin in place. Also provided are wound closure systems that comprise one or more microstructure wound closure devices along with other components, such as protective covers and wound healing therapeutics. A variety of packaging specifications are disclosed, as is dispenser apparatus configured to enable simple one-handed application of the wound closure devices. Methods described herein provide for the closure of various wounds with the wound closure devices and systems.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No.61/660,561, filed on Jun. 15, 2012, and U.S. Provisional Application No.61/710,246, filed on Oct. 5, 2012, both of which are herein incorporatedby reference in their entirety.

BACKGROUND

Compositions and methods for wound closure are known in the art.Depending on the severity of the wound, the most common treatments rangefrom simple adhesive-based, over the counter products, such asBAND-AIDs®, butterfly strips, and Steri-Strips, to more specializedproducts, such as sutures and staples. Proper application of sutures andstaples requires a trained specialist; and although these techniques canbe quite effective at closing wounds, they are invasive, and painfulprocedures that frequently require the use of an anesthetic.Furthermore, these procedures can leave unsightly scars, both from thesecondary insertion holes as well as spacing and depth variations thatresult in varying tensions applied, to the laceration or surgicalincision between the suturing points and intervening spaces. Moreover,these skin closure techniques necessitate follow-up visits to a hospitalor doctor's office for removal of sutures and staples; a particularlysub-optimal feature in the event of an infection, wherein it is oftennecessary to remove the sutures such that the wound may be reopened andcleaned. Additionally, simply covering the wound with a bandage, such asa BAND-AID® is often not sufficient to close more severe or deeperwounds; the adhesives used to attach these devices and the Steri-Stripsand butterfly strips are not adequate to close these wounds withoutdetaching or creep. Skin moisture adds to the problem by furtherreducing adherence of the adhesive based bandage, and may lead to theirpremature release from the skin and wound site before closure of thewound and proper healing. Also, the adhesive can induce symptomaticallergic and inflammatory reactions.

The present invention relates to improved wound closure devices that insome embodiments enable simple, minimally invasive wound closure,without the need for follow-up care. The devices are easily applied andremoved, often with little to no pain, thus obviating reliance ontrained specialists for their application and removal. In someembodiments, the devices of the present invention can achieve woundclosure without resulting in the aforementioned closure-induced scarringthat can occur with the prior art techniques. Furthermore, in certainembodiments the wound closure devices disclosed herein may beappropriately secured to a wound without the need for adhesive, thusavoiding potential allergic complications,

Summary

The present invention relates generally to wound closure devicescomprising one or more microstructures. In some embodiments, themicrostructures are capable of penetrating into skin or tissue. In someembodiments, the device comprises a plurality of microstructures. Themicrostructures are fabricated on, affixed to, or connected to a base orbacking that may optionally be made out of the same material as themicrostructures, or a different material. In some embodiments, the baseor backing is flexible, stretchable, or both flexible and stretchable.In some embodiments, the microstructures are fashioned into one or moremicrostructure arrays, upon a base. In particular embodiments, the woundclosure devices comprise at least two microstructure arrays, each arraybeing patterned upon a base (said base optionally comprising one or morearrays), and said arrays optionally being affixed to a backing,according to the present disclosure. In such embodiments, at least oneof said arrays is capable of securing the device on one side of a wound,and at least one other of said arrays is capable of securing the deviceon another side of the wound. In other particular embodiments, the woundclosure devices comprise only one microstructure array, said arrayfabricated on a base portion, and said base portion optionally beingaffixed to a backing. In such embodiments, at least one of themicrostructures comprised in the array is capable of securing the deviceon one side of the wound and at least one other microstructure comprisedon the array is capable of securing the device on the other side of thewound.

Devices of the present invention are useful wound closure products,capable of performing a variety functions (e.g., protecting a wound fromits surrounding environment, preventing infection, closing a wound, andincreasing the delivery of therapeutic compounds through skin).

In particular embodiments, the devices are specifically designed suchthat their application does not result in inflammation. In someembodiments, the wound closure devices disclosed herein induce little tono inflammation and result in little to no additional scarring (e.g.,the railroad track effect that results from staples and sutures). Insome embodiments, the devices of the present invention have theimportant advantage of being easily applied and removed without the needfor extensive training or specialized equipment. Furthermore, in certainembodiments, the devices are secured to the skin of a patient in theabsence of an adhesive, avoiding allergic reactions caused by adhesives.Thus, the wound closure devices of the present invention provide anattractive and versatile alternative to traditional wound closuredevices.

In some embodiments, the wound closure devices of the present inventioncomprise a flexible and/or stretchable backing upon which one or moremicrostructures are affixed. In some embodiments, one or moremicrostructure arrays are affixed to a flexible and/or stretchablebacking. The flexibility and/or stretchability of the backing may beuniform throughout; or, optionally one or both of these properties mayvary across, or along, the device, a microstructure array, or betweentwo or more microstructure arrays.

In some embodiments, the wound closure device of the present inventioncomprises one or more microstructure arrays, optionally affixed to abacking, such that at least one microstructure array is capable ofpenetrating into skin or tissues. In particular embodiments, suchdevices comprise microstructures that penetrate into the superficialepidermis, epidermis, superficial dermis, or deep dermis. In otherembodiments, the wound closure device comprises a plurality ofmicrostructure arrays such that the microstructures do not penetrate theskin or tissue surface.

In certain embodiments, the wound, closure devices may comprise at leasttwo microstructure arrays as described herein, said arrays beingoptionally affixed to a backing. In some particular embodiments, thewound closure devices may comprise two or more arrays optionally affixedto a backing, as described herein, such that at least two arrays areseparated by space with no arrays. This space, referred to throughout asan “Isthmus”, may be of any suitable length, width, or shape, and may becomprised of any suitable material. In some embodiments, the isthmusranges from 1 mm in length to 15 mm in length. In certain embodimentsthe isthmus is not stretchable, while in other embodiments this space isstretchable.

In some embodiments, the wound closure devices of the present inventioncomprise one or more microstructures at an angle with respect to a baseor backing. In one such embodiment, microstructures are angled in a wayto translate the longitudinal tension from the skin pulling the woundapart along the device into a force that pushes the device downward ontothe skin, thus, e.g., effectively anchoring the device onto the skin.Wound closure devices of the present invention may in some embodimentsalso include microstructure arrays comprising microstructures withvariable angles relative to a base, e.g., wherein at least twomicrostructures comprised in a single array extend from a base atdifferent angles than one another. A non-limiting example of such anarray, e.g., is one that comprises both straight microstructures (i.e.,protruding from a base at a 90° angle) and angled microstructures (e.g.,protruding from the base at an angle less than 90°, such as 51°).Additionally, individual microstructure length can vary based upon itsposition in a microstructure array, or based upon its position on awound closure device.

In various embodiments, the microstructure arrays of the presentinvention are fashioned or affixed upon a base in a particular shape orpattern, said shape or pattern optionally being of any shape or geometrydescribed herein. In some embodiments, such patterned arrays are furtheraffixed to a backing (e.g., a flexible and/or stretchable backing);while in other embodiments they are not. In some certain embodiments,arrays according to the present disclosure are fashioned or affixed on abase portion, optionally at an angle, wherein the arrays are patternedin a rectangular shape, said arrays comprising microstructures of anyshape or geometry described herein; and said arrays optionally beingaffixed to a backing.

In some certain embodiments, the wound closure devices of the presentinvention comprise a plurality of microstructure arrays that are capableof penetrating or grasping skin or tissue; said arrays either beingaffixed to a flexible and stretchable backing, or being comprised on asingle flexible and stretchable base, in a configuration such that atleast two arrays are separated by an isthmus, as described herein; andsaid devices having the capability of being stretched across a wound andsecured on either side via the traction or grip of the microstructures.Accordingly, such a device may be applied by first securing at least onemicrostructure array to the skin or tissue on one side of the wound,then stretching the device across the wound so as to secure anothermicrostructure array to the skin or tissue on the other side of thewound. In such a manner, the retractile force of the stretched devicecan in some embodiments pull and/or secure the wound closed, thusfurther promoting healing; while in other embodiments such a forcestabilizes the position of the device on the skin, but does not directlyinduce the closure of the wound.

In other certain embodiments, the wound closure devices of the presentinvention comprise a plurality of microstructure arrays that are capableof penetrating or grasping skin or tissue; said arrays either beingaffixed to a non-stretchable backing, or being comprised on a singlenon-stretchable base, in a configuration such, that at least two arraysare separated by an isthmus, as described herein. In such embodiments,the devices are useful e.g., for securing tissue in place. Non-limitingexamples of how this type of device may be used include the securing ofa wound closed that has already been closed by some other method e.g.,via suturing, or with forceps.

The wound closure devices of the present invention may optionally becovered to further protect the lesion from the surrounding environment,and to assist in maintaining proper securing of the device as placed.Covers may optionally comprise adhesive.

The wound closure devices of the present invention may comprisemicrostructures of various shapes, sizes, and structures. Accordingly,in some embodiments, one or more microstructure arrays are fashioned,optionally upon a base, said microstructures optionally comprising avariety of shapes, sizes, structures, and geometries; and said arraysoptionally being affixed to a backing. Certain embodiments provide formicrostructures selected from the group consisting of microneedles,microblades, microanchors, microfishscale, micropillars, microhairs, andcombinations thereof. The wound closure devices of the presentinvention, may comprise microstructure arrays comprising any density ofmicrostructures. In some embodiments, the density of microstructurescomprised in an individual array varies from 2 microstructure per array,to more than 1000 microstructures per array. In certain embodiments, thearrays comprise a density of microstructures arrays varying from 1microstructure per cm² to 1000 microstructures per cm². Accordingly, invarious embodiments the array pitch is varied from approximately 30 μmto more than 1 cm.

The microstructures comprised in the wound closure devices disclosedherein may be made of any material or mixture of materials, in someembodiments, the material is a natural material, or a mixture of naturalmaterials; while in other embodiments it is a synthetic material, or amixture of synthetic materials. Still other embodiments provide formicrostructures, according to the present disclosure, comprisingmixtures of one or more synthetic materials and one or more naturalmaterials. In particular embodiments, microstructures are made of amaterial selected from a polymer, a metal, a biomaterial, and acombination thereof. In some embodiments, a microstructure of thepresent invention is comprised of nanostructures, (e.g., nanofibers). Insome embodiments, the microstructures are coated with nanostructures(e.g., nanofibers). In some embodiments the microstructures arecomprised of, or consist essentially of biodegradable materials. In someembodiments this is very important to ensure complications, such asinflammation, tissue damage, and infection, due to broken needles do notoccur. In other embodiments, the microstructures do not comprisebiodegradable materials. In other embodiments the microstructurescomprise biodegradable materials and non-biodegradable materials.

In certain embodiments, microstructures of the present invention arecomprised of a polymer selected from poly(methyl methacrylate) (PMMA),silicon, and chitin.

The wound closure devices of the present invention may also optionallycomprise other components such as, but not limited to, nanostructures(e.g., nanostructure arrays or nanofibers); bioactive compounds (e.g.,drugs, therapeutics, hydrogels, healing substances, and combinationsthereof), etc. In some particular embodiments, the wound closure devicesfurther comprise chitin (e.g., chitin nanofibers). In other embodimentsthe wound closure devices of the present invention further comprise ahydrogel.

Some embodiments of the present invention provide for microstructurearrays designed to penetrate the skin to enable delivery of drugs orother therapeutic agents. In one particular embodiment, themicrostructures are long enough to penetrate the skin, but not deepenough to reach nerve endings that cause pain. Some embodiments canincorporate both microstructures coated with drugs as well asmicrostructures with open internal structure in which drugs can beincorporated.

In some embodiments, the wound closure device is applied to the skinwithout the use of an applicator or instrument. In other embodiments,the wound closure device is applied to the skin using an applicator orinstrument, such as a forceps or tweezers, to hold the device, or toprovide assistance in delivering force during the application of thedevice over the wound.

In some embodiments, the wound closure devices of the present inventionmay optionally include adhesive to assist in the application andoptionally in the stabilization of the device upon the skin. Adhesivemay be present on the device in any suitable location. In someembodiments, the wound closure devices comprise an adhesive backing, ora base that comprises adhesive.

In some embodiments, adhesive is provided to the device on, a tab thatis attached to at least one end of the device. The tab is not part ofthe device but is attached to the device in order to enable adhesion.The device actually remains on the wound, while a tab can be removed.The tabs can be added to one or both distal ends of the device. In otherembodiments, adhesive is provided on a tab that is attached to at leastone side of the device.

Still other embodiments provide for devices as described hereincomprising adhesive tabs positioned on at least one end and at least oneside of the device. These adhesive tabs may be any length, optionallybeing shorter, longer, or equal in length to any one or more sides ofthe device. Furthermore, some embodiments provide for adhesive tabs thatare removable, e.g., adhesive tabs comprising perforations that enablethe adhesive portion to be easily torn off by hand. In some embodimentsthe adhesive is any medical grade adhesive, such as, e.g., an acrylate(such as, e.g., is used on the Steri-Strips or Steri-Strip S isthmus),or hydrogel-based adhesives that can stick to wet surfaces (e.g.,Polyethylene glycol (PEG) hydrogel). In other embodiments the adhesivecomponent comprises nanostructures that provide glueless adhesion.Adhesion of a device to skin or tissue induced by such adhesives maylast for as little as a minute (e.g., when the adhesive is utilized tohelp apply the device) or such adhesion may last for 10 days or more.Accordingly, adhesion to the skin or tissue as the result of an adhesivemay last for 5 min, 10 min, 15 min, 20 min, 30 min, 60 min, 2 hr 4 hr, 6hr, 12 hr, 24 hr, 2 days, 4 days, 6 days, 8 days, 10 days, or more,including all integers (31 min, 32 min, 33 min, 13 hr, 14 hr, 15 hr, 3day, 5 days, etc.) and ranges (1 min-10 days, min-1 hr, 5 min-20 min,etc.) of the adhesion durations set forth herein.

Embodiments of the present invention provide for wound closure devicesas disclosed herein that are available in a single package comprisingonly one such device, as well as packages comprising a plurality of saiddevices. In one embodiment, the wound closure devices are in the form ofa roll, said roll optionally comprising individually wrapped woundclosure devices, or alternatively a plurality of wound closure devicesthat are not individually wrapped. In particular embodiments, thedevices are sterile, and are packaged so as to maintain such sterilityuntil being opened.

The present invention furthermore provides for hand held dispensers thatallow for easy application of the wound closure devices of the presentinvention. In one embodiment, the dispenser is a roll-on, handhelddispenser, optionally enabling rapid single hand operation.

Some embodiments of the present invention further provide for a kitcomprising a wound closure system. Wound closure systems comprise one ormore wound closure devices, as described herein, as well as otheroptional components such as, e.g., one or more cover (optionallycomprising adhesive) to be applied over the wound closure device; one ormore containers (e.g., bottles, pouches, packets, tubes) comprising adrug or therapeutic which can optionally be applied to the wound priorto the application of the device; cleansing and/or sterilization means(e.g., antiseptics, antibiotics, sterile saline); analgesics (e.g.,Benzocaine or Lidocaine); and instructions for using the variouscomponents of the wound closure system singly, or in combination.

The wound closure devices of the present invention are suitable fortreating internal and external wounds alike, in some embodiments, thewound closure devices are applied to a subject's skin; and in otherembodiments the wound closure devices are applied to a subject's tissue(e.g., internal tissue). Accordingly, the wound closure devices of thepresent invention find utility in a variety of settings including, butnot limited to, the treatment of wounds in urgent care settings (e.g.,surgery or trauma centers including emergency rooms, operating rooms,ambulances battlefields, and sites of accidents); in hospitals andclinics; in over the counter settings (e.g., for use at home).

In some embodiments, the wound closure devices of the present inventionhave alternative utilities. For example, the devices disclosed hereinmay also be used in cosmetics, wherein microstructures, as describedherein, may be used to penetrate the skin producing skin rejuvenationvia acute injury resulting in stimulating the dermis and collagenformation inducing effects achieved with cosmetic laser procedures andskin rollers made of microneedles. This achieves improvement in theappearance of the skin by reducing wrinkles and increasing skin volume.In contrast to cosmetic laser procedures, application of the woundclosure devices do not produce symptomatic inflammation resulting inpain, redness, swelling and temporary disfigurement; symptoms which canpresent for up to a few days after the laser procedure. In contrast torollers made of microneedles, the wound closure devices can be appliedto regions of the skin that are not easily accessible to microneedles,such as between the nose and mouth. In addition, our wound closuredevices can be applied and left in place overnight or for dayspotentially providing more stimulation to the dermis than is achievedwith abort-term treatment with a microneedle roller. Finally, the woundclosure device generates more uniform distribution of holes in the skinthan can be achieved with a microneedle roller which is rolled onto theskin surface.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1a to 1f show a schematic representing a representative replicamolding process for fabrication of microneedles. FIG. 1a : A master ofthe desired dimensions is made with a metal, silicon, or a polymer viamicromachining, microlithography, etching, laser cutting, or acombination thereof. FIG. 1b : The master is replicated using apolymeric material, for example silicone, to form a mold. FIG. 1c : Themold is separated from the master. FIG. 1d : The mold is filled with asolution or a melt of the microstructure material (e.g., by drop castingor spraying). FIG. 1e ; The microstructure material is solidified (e.g.,cured or dried). FIG. 1f : The microstructures are separated from themold.

FIGS. 2a to 2c illustrate examples of microneedles made from apolymethylmethacrylate (PMMA) solution in acetone with replica moldingof an aluminum master and a silicone mold. Microneedle dimensions areprovided.

FIGS. 3-1 to 3 a-6 schematically illustrate examples of microneedles aspart of an array of microneedles specifically designed for woundclosure. Note the asymmetric microneedle shape designed to avoid themicroneedle lifting out of the skin when tension is applied to, oroccurs on, the wound. FIG. 3b is a table with exemplary microneedledimensions.

FIGS. 4a to 4d schematically illustrate a microneedle.

FIG. 5a schematically illustrates a microstructure (e.g., a microneedleor microblade) angled and proportioned such that a line extending fromthe tip perpendicular to the base does not pass through the foundation.FIG. 5b schematically illustrates a microstructure (e.g., a microneedleor microblade) angled and proportioned such that a line extending fromthe tip perpendicular to the base passes through the foundation.

FIG. 5c schematically illustrates a microstructure similar to FIG. 5a inpartial-phantom perspective view,

FIG. 6a schematically illustrates an angled microstructure.

FIG. 6b schematically illustrates a curved microstructure.

FIG. 6c schematically illustrates an articulated microstructure.

FIG. 6d schematically illustrates a curved microstructure.

FIGS. 7a and 7b show a comparison of (FIG. 7a ) a low density straightmicroneedle array comprising 12 needles of 1 mm height in a 3 mm pitchformation in a 7 mm×10 mm array and (FIG. 7b ) a high density straightmicroneedle array comprising 28 needles of a 1 mm height with a uniformpitch of 1.5 mm in a 6 mm×10 mm array.

FIGS. 8a -1 to 8 a-6 schematically illustrate examples of microblades aspart of an array of microblades specifically designed for wound closure.Note the asymmetric microblades shape designed to avoid the microbladeslining out of the skin when tension is applied to, or occurs on, thewound. FIG. 8b is a table with exemplary microblade dimensions.

FIGS. 9a to 9d schematically illustrate a microblade of type 1 MB (oneof the examples from FIG. 8b ).

FIGS. 10a to 10d schematically illustrate a microblade of type 2 MB (oneof the examples from FIG. 8b ).

FIGS. 11a to 11d schematically illustrate a microblade of type 3 MB (oneof the examples from FIG. 8b ).

FIGS. 12a and 12b show a comparison of (FIG. 12a ) a low density angledmicroblade array comprising 6 needles that are 900 μm in height in a 4.5mm pitch formation in a 6 mm×10 mm array and (FIG. 12b ) a high densityangled microblade array 900 μm in height with a uniform pitch of 1.5 mm.

FIGS. 13a to 13e show schematic drawings of an exemplary wound closuredevice with angled needles made with a silicone backing and high-densityneedle arrays. Note the optional addition of a microstructure coating(e.g., a coating with a wound healing agent).

FIGS. 14 to 14 c are images of an exemplary wound closure devicecomprising a PMMA microstructure array of straight microneedles mountedon a silicone backing.

FIGS. 15a to 15e show schematic drawings of an exemplary device made ofa polyurethane backing, with two PMMA microneedle arrays comprisingmedium density needles. Note the narrow isthmus, the option of includingadhesive surrounding the needle arrays, and the option of addingchitosan hydrogel on the isthmus.

FIG. 16 shows a schematic representation of a wound closure device ofthe present invention applied to a wound (cross sectional view). In thisembodiment, the microneedles penetrate through the epidermis and intothe dermis keeping the wound closed. This is essentially the same actionas a suture or a staple, but significantly less injurious to tissues.The deep tissue suture may or may not be required depending on theconditions of the wound.

FIGS. 17a to 17c are photographs of three non-limiting examples of thepresent wound closure devices. Note the different sizes, shapes, anddimensions of the backings (1), isthmuses (2), bases (3), arrays (4),array spacing (5), etc. (FIG. 17a ) shows a device comprising apolyurethane backing, with a polyester filament as an isthmus. Themicrostructures are spaced at a 1 mm pitch. (FIG. 17b ) shows a devicewhich comprises a backing and isthmus that are both made of polyester.The microstructures are at a uniform pitch of 1.5 mm, (FIG. 17c ) showsa device comprising a backing and isthmus both made of a paper/fibermixture with added polyester filament supports for strength. Themicrostructures are at a uniform pitch of 1.5 mm.

FIGS. 18a and 18b are photographs of the devices shown in FIG. 17c ,when applied on a human volunteer, both with and without a protectivecover. These devices comprise PMMA microneedles affixed to a Steri-Stripadhesive tape. Note the wrinkling of the skin in the middle of thedevice demonstrating the ability of the device to successfully stretchthe skin documenting the device's ability to apply lateral tension onthe skin, which is important for closing a wound. This indicates thedevice is capable of closing a wound.

FIG. 19 is a photograph of one non-limiting example of the present woundclosure devices. In this embodiment, the device comprised two PMMAmicroneedle arrays on PMMA bases that were glued onto an inelasticbacking of polyethylene derived from Steri-Strip S. The photograph showsthe device as applied on a silicone skin simulator with an incision madein it, and placed under tension, additionally with an adhesive cover.

FIG. 20 is a photograph of a device, as described in FIG. 19, placed onthe wrist of a human volunteer and protected by an adhesive cover.

FIG. 21 shows data from an experiment testing the traction of angledneedles applied on fresh porcine skin. A 15 mm×28 mm segment ofSteri-Strip S with 8 mm×12 mm array of C2 needles (8×4 needles of thetype illustrated in FIG. 2b ) was pulled against a 2.5×2.5 cm piece ofporcine skin glued onto a Plexiglass slide. Porcine skin was rinsed with0.9 wt % saline solution, cut to 2-3 mm thick, and then glued to amicroscopic slide. Porcine skin was rinsed again with saline solutionand patted dry with gauze prior to testing. Traction was measured with atensile tester by mounting the needle array on one side of the testerand the skin on the other. The Y axis of the graph is force measured inNewtons, and the X axis is displacement measured in millimeters.

FIGS. 22a to 22c illustrate the location of wounds, which were createdon a neonatal porcine for use in a pre-clinical study of the woundclosing efficiency of the devices of the present invention. This studyis fully described in Example 4. (FIG. 22a ) shows a schematic of thesize of the wounds and their locations on the porcine. (FIG. 22b ) showsa photograph of the animal prior to wound creation, with numbers placednear the incision sites. (FIG. 22c ) shows a representative example ofone of the wounds, prior to closure.

FIG. 23 shows results of the preclinical study described in FIGS. 22a to22c (see Example 4). Two wounds were closed with microstructure arraywound closure devices as described herein, and one wound was closed withsutures Wounds were observed for 12 days, and photographs from Day 0(before wound closure). Day 1 (one day after wound closure), Day 6, andDay 9 (undressed wound—i.e. devices and covers removed from wound) areshown. On Day 9, no abnormalities were observed on or around the woundstreated with the microstructure array closure devices, however the woundclosed with sutures showed both inflammation and erythema (Draize Scoreof 2 on scale of 0-4).

FIG. 24 is an image from Day 9 of the undressed (device and coverremoved) wound that was treated with Device A, which comprised twostraight-needle microstructure arrays.

FIG. 25 is an image from Day 9 of the undressed wound that was treatedwith Device C, which comprised two angled needle microstructure arrays.

FIG. 26 is an image from Day 9 of the undressed wound that was treatedby suturing.

DETAILED DESCRIPTION

The particulars shown herein are by way of example and for purposes ofillustrative discussion of the preferred embodiments of the presentinvention only, and they are presented in the cause of providing what isbelieved to be the most useful and readily understood description of theprinciples and conceptual aspects of various embodiments of theinvention. In this regard, no attempt is made to show structural detailsof the invention in more detail than is necessary for the fundamentalunderstanding of the invention, the description taken with the drawingsand/or examples making apparent to those skilled in the art how theseveral forms of the invention may be embodied in practice.

Definitions and Abbreviations

The terminology used herein is for the purpose of describing particularembodiments only, and is not intended to limit the scope of the presentinvention, which will be limited only by the appended claims. Unlessdefined otherwise, all technical and scientific terms used herein havethe same meaning as commonly understood by one of ordinary skill in theart to which this invention belongs. As used in the specification andappended claims, unless specified to the contrary, the following termshave the meaning indicated.

As used herein and unless otherwise indicated, the terms “a” and “an”are taken to mean “one”, “at least one” or “one or more”. Unlessotherwise required by context, singular terms used herein shall includepluralities and plural terms shall include the singular.

Reference to the term “e.g.” is intended to mean “e.g., but not limitedto” and thus it should be understood that whatever follows is merely anexample of a particular embodiment, but should in no way be construed asbeing a limiting example. Unless otherwise indicated, use of “e.g.” isintended to explicitly indicate that other embodiments have beencontemplated and are encompassed by the present invention.

By “about” is meant a quantity, level, value, number, frequency,percentage, dimension, size, amount, weight or length that varies by asmuch as 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1% to a referencequantity, level, value, number, frequency, percentage, dimension, size,amount, weight or length. It any embodiment discussed in the context ofa numerical value used in conjunction with the term “about,” it isspecifically contemplated that the term about can be omitted.

Unless the context requires otherwise, throughout the presentspecification and claims, the word “comprise” and variations thereof,such as, “comprises” and “comprising” are to be construed in an open,inclusive sense, that is as “including, but not limited to”.

By “consisting of” is meant including, and limited to, whatever followsthe phrase “consisting of.” Thus, the phrase “consisting of” indicatesthat the listed elements are required or mandatory, and that no otherelements may be present.

By “consisting essentially of” is meant including any elements listedafter the phrase, and limited to other elements that do not interferewith or contribute to the activity or action specified in the disclosurefor the listed elements. Thus, the phrase “consisting essentially of”indicates that the listed elements are required or mandatory, but thatother elements are optional and may or may not be present depending uponwhether or not they affect the activity or action of the listedelements.

Reference throughout this specification to “one embodiment” or “anembodiment” or “some embodiments” or “certain embodiments” mean that aparticular feature structure or characteristic described in connectionwith the embodiment is included in at least one embodiment of thepresent invention. Thus, the appearances of the phrases “In oneembodiment” or “in an embodiment” or “In certain embodiments” in variousplaces throughout this specification are not necessarily all referringto the same embodiment. Furthermore, the particular features,structures, or characteristics may be combined in any suitable manner inone or more embodiments.

“Optional” or “optionally” means that the subsequently described eventof circumstances may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not.

“Substantially” or “essentially” means nearly totally or completely, forinstance, 95% or greater of some given quantity.

As used herein, the term “wound closure device” as used generally meansa device used for closing a wound, covering a wound, protecting a wound,a wound dressing, a bandage, etc.

As used herein, the term “wound” means an injury to tissue or skincaused by a scrapes, cuts, abrasion, surgical procedures (e.g., causedby minimally invasive surgery, laparascopic surgery, robotic surgery,incisional biopsies, general surgery, and cosmetic surgery), denudedskin, burns, ulcers (e.g., diabetic ulcers, ulcers from vascularinsufficiency, pressure sores, and burns), or other skin problems (e.g.,allergies). Wound may range from superficial (e.g., affecting merely theepidermis) to more traumatic (e.g., lesions which affect layers of skinor tissue at depths which are beneath the epidermis). Wounds may be ofany length or shape, e.g., in some embodiments, wounds are straight,jagged or curved.

As used herein, the term “tissue” means any human or other animal tissueincluding, but not limited to skin, muscle, tendon, bone, heart, lung,kidney, brain, bowel, colon, rectum, stomach, esophagus, etc.

Reference to the term “PMMA” as used herein is meant to refer topoly(methyl methacrylate), which is also known as Poly(methyl2-methylpropenoate (IUPAC name), polymethyl methacrylate, or morecommonly known as Plexiglass™.

The terms “affixed” and “attached” are used interchangeably throughout,and have their ordinary meaning, e.g., being connected or fastened tosomething else.

Accordingly, other terms such as “connected”, “fastened”, and “bound”may also be used in a similar manner.

The term “everted” or “eversion” as used herein is intended to have itsnormal medical meaning, e.g., in regard to the eversion of a wound.Accordingly, an everted wound refers to a wound that is closed (or atleast substantially closed), wherein the wound edge is slightly raisedabove the normal skin level. Wound edge eversion is a common suturingtechnique to reduce the formation of linear pits and visible scarring.

The term “grasping” is used herein, to describe a microstructure-basedanchoring of a wound closure device to its intended location on thesurface of the skin or tissue to which it is applied; said anchoring notrequiring penetration into the skin or tissue by the microstructures,but instead e.g., being anchored via friction generated by the contactof the microstructures with the skin or tissue. In some embodiments, thedevice is anchored by grasping, optionally with or without theassistance of the other various components of the present wound closuredevices and systems, e.g., a protective cover or adhesive. The term“penetration” or “penetrate” is meant herein to refer to the action ofpiercing the skin or tissue, e.g., with one or more of themicrostructures disclosed herein.

The term “inflammation” is meant to have its ordinary medical meaning,i.e. a biological response of a tissue to a harmful stimulus. Commonsigns of inflammation include pain, heat, redness (erythema), swelling(edema), and loss of function.

The term “base” is meant generally to describe a supporting means fromwhich one or more microstructures protrude. In some embodiments, thebase comprises a plurality of microstructures; and in other embodimentsdevices comprising singular microstructures on a base are provided. Thebase may be a separate component upon which one or more microstructuresare affixed; or alternatively, the microstructures and the base may beone continuous component that are fabricated at the same time,optionally from the same or different materials. For example, but not tobe limited in any way, some embodiments of the present invention providefor wound closure devices comprising one or more microstructure arrayspatterned on a base, wherein both the base and the microstructures aremade out of PMMA. In one such embodiment, the microstructures aremanufactured using a replica molding technique, wherein both themicrostructures and the array are manufactured simultaneously, and arethus in essence one single component (See FIGS. 1a to 1f ). Furtherembodiments provide for a variety of base specifications including,e.g., thickness, length, width, and composition. In certain embodiments,the base comprises a substantially planar upper surface and asubstantially planar lower surface; said upper surface comprising one ormore microstructures, and said lower surface optionally being affixed toa backing, in such an embodiment, the upper surface comprising themicrostructures is intended to be put in contact with the skin or tissueof the patient and the lower surface is intended to be exposed to theexternal environment, or optionally to be in contact with a protectivecover, e.g., a cover comprising adhesive.

The term “array” and “microstructure array” are used hemin to describe atwo-dimensional configuration of two or more microstructures on a“base”, as described herein, said base having a substantially planarupper surface from which the microstructures protrude. The “array” maybe in any suitable shape or pattern, and the array may be of anysuitable size or dimensions. Furthermore, arrays may comprise anysuitable number or density of microstructure, said microstructuresoptionally extending from the base at angle, or in a substantiallyperpendicular manner.

An “array region” as used herein is meant to describe an area of thepresent devices upon which one or more microstructure arrays areaffixed. Accordingly, in some embodiments the array region is a portionof the backing upon which one or more bases are affixed, said bases eachcomprising one or more microstructure or microstructure arrays. In someparticular embodiments, the devices of the present invention comprise atleast two “array regions” that are separated from one another by anisthmus, as described herein. A non-limiting example of such a design isshown in FIGS. 13a to 13e ; wherein a wound closure device is depicted,said device comprising two array regions, each region comprising onemicrostructure array affixed to a backing; wherein the two array regionsare separated by an isthmus of the exact same width as the backing.Another similar non-limiting example is shown in FIGS. 15a to 15e ,wherein the device comprises two array regions separated by an isthmuswith a narrow width compared to the width of the backing upon which thearrays are affixed.

The term “isthmus” as used herein refers to a space with no arrays, thatseparates two or more microstructure “arrays” or “array regions”“Isthmus separation” refers to the distance separating two arrays onopposing sides of an isthmus. The isthmus may comprise any suitablematerial, and may in some embodiments be rigid, flexible, and/orstretchable. The size and shape of the isthmus may vary, and in someembodiments the device will comprise an isthmus and a backing, bothbeing made out of the same material, while in other embodiments thematerial comprised in the isthmus will differ from that of the backing.In certain embodiments, the isthmus is simply created by affixing, twoor more microstructure arrays upon a backing such that a space separatesthe two arrays. In still other embodiments, the isthmus is a portion ofa base comprising a plurality of microstructure arrays (i.e., theisthmus and the microstructures are made of the same material).Non-limiting examples of two different types of isthmuses can be seen inFIGS. 13a to 13e and 15a to 15e wherein the shape, composition (siliconevs. thermoplastic polyurethane (“TPU”)), and properties (i.e.stretchable vs. non-stretchable) have been varied. Furthermore, FIGS.15a to 15e demonstrate the optional addition of a therapeutic (e.g., 2%Chitosan hydrogel) to the isthmus to further promote wound healing. Insome embodiments, the isthmus ranges from 1 mm in length to 15 mm inlength. Accordingly, in these embodiments, the devices of the presentinvention may comprise isthmuses that are 1 mm in length, or they maycomprise isthmuses that are 2 mm 3 mm; 4 mm; 5 mm 6 mm; 7 mm; 9 mm 9 mm;10 mm; 11 mm; 12 mm; 13 mm; 14 mm; or 15 mm in length, including alldecimals (e.g., 1.5 mm, 1.6 mm, 1.7 mm, etc.) and ranges (e.g., 1-15 mm,5-10 mm, 10-15 mm, 3-4 mm, 5-6 mm, 6-8 mm, etc.) in between, of theisthmus lengths set forth herein. The width of the isthmus may vary. Insome embodiments the isthmus width is the same as the base or backing ofthe device. In other embodiments, the isthmus is wider or narrower thanthe base or backing of the device. Thus, the width of the isthmus mayrange from as small as 1 mm to as large as 50 cm or more. Accordingly,isthmus widths may range from approximately 1 mm, 2 mm, 3 mm, 4 mm, 5mm, 6 mm, 7 mm, 8 mm, 9 mm, cm, 2 cm, 3 cm, 4 cm 5 cm, 10 cm, 20 cm, 30cm, 40 cm, 50 cm, or longer, including all integers (e.g., 11 mm, 12 mm,13 mm, etc.) and ranges (e.g., 2 mm-50 cm, 5 mm-15 mm, 5 mm-10 mm, etc.)in between of the isthmus widths set forth herein.

As used herein, when components of the wound closure devices are said tobe positioned or distributed “anisotropically”, it is meant that thecomponents are not uniform throughout, but instead their properties varydirectionally. Thus, e.g., in some embodiments, anisotropic positioningrefers to variation in the components of individual microstructurescomprised in a microstructure array, said microstructures comprisingdirectional variability in their physical properties, e.g., their aspectratios or angles of attachment to a backing. In other embodiments, thisvariability may be in regard to directional differences betweendifferent arrays. Anisotropic variability may be in one direction, or inmore than one direction.

As used herein, the term “microstructure” refers to a three-dimensionalstructure projecting from or connected to a base. A microstructure maybe an integral part of the base (i.e., the microstructure and base aremonolithic). Alternatively, the microstructure may be of separateconstruction than the base but be joined to the base (e.g., throughadhesive, bonding, etc.).

Microstructures typically have dimensions on the micron size scale,although certain dimensions may extend into the millimeter size scale(e.g., length) and certain dimensions may be smaller than one micron(e.g., nano scale tip width).

Representative microstructures include microneedles, microblades,microanchors, microfishscale, micropillars, and microhairs.

A microstructure includes a foundation, a tip, and a body joining thefoundation with the tip.

As used herein, the term “foundation” refers to the two-dimensional areawhere the base meets the microstructure. The foundation may be betterunderstood with reference to FIGS. 5a and 5c . The foundation can be anytwo-dimensional shape, including a circle, oval, ellipse, triangle,rectangle, square, quadrilateral, or higher-order polygon.

As used herein, the term “tip” refers to the end of the microstructuredistal to the foundation and base. The tip may be a singe point (e.g., aneedle), a line (e.g., a blade), or other shape.

As used herein, the term “body” refers to the portion of themicrostructure between the foundation and the tip. The body may bebetter understood with reference to FIGS. 5a and 5c . The body may alsobe referred to herein as a “shaft” of the microstructure. The body has a“length” that is equal to the longest distance connecting a point on thefoundation to the tip.

The microstructure can be either straight or curved. In certainembodiments, the body connects the foundation to the tip withoutcurvature along its length, in other embodiments, the body is curvedalong its length between the foundation and the tip.

As used herein, the term “straight” refers to a microstructure having nocurvature (i.e., no concave or convex surfaces) along the body betweenthe foundation and the tip Examples of straight microstructures areillustrated schematically in FIGS. 4a to 6a and photographically inFIGS. 2a and 2 c.

As used herein, the term “curved” refers to a microstructure having oneor more concave or convex surfaces along the body between the foundationand the tip. Examples of curved microstructures are illustratedschematically in FIGS. 6b and 6d and photographically in FIGS. 2b, 12a ,and 12 b.

Straight and curved microstructures can be defined in terms of a “faceangle” (θ_(F)), which is the smallest angle formed between the base andthe microstructure. Referring to the straight microstructure illustratedin FIG. 6a , the face angle is constant along the entire body from thefoundation to the tip. The curved and articulated microstructures inFIGS. 6b and 6c , respectively, include multiple different face anglesalong the body, as illustrated by comparing Angle θ₁, formed between thebase and tangent T₁, to Angle θ₂, formed between the base and tangentT₂. Angle θ₁ is different than Angle θ₂. The face angle will always begreater than the overall angle of the microstructure. In certainembodiments, the face angle is greater than 90 degrees (e.g., for astraight microstructure at 90 degrees relative to the base). In certainembodiments, the face angle is less than 90 degrees. In one embodiment,the face angle is from 5-90 degrees. In one embodiment, the face angleis from 10-80 degrees. In one embodiment, the face angle is from 20-70degrees. In one embodiment, the face angle is from 50-70 degrees.

As used herein, the term “articulated” refers to a microstructure thatdoes not curve continuously but instead curves via one or more jointsconnecting straight portions.

An articulated microstructure may also be referred to as “beveled.” Anarticulated microstructure is illustrated in FIG. 6 c.

As used herein, the term “convex” refers to a microstructure having atleast one line along the outer surface of the body that deviatesoutwardly from a straight line between the foundation and the tip. Anexemplary convex microstructure is illustrated in FIG. 6 d.

As used herein, the term “concave” refers to a microstructure having atleast one line along the outer surface of the body that deviatesinwardly from a straight line between the foundation and the tip. Anexemplary concave microstructure is illustrated in FIG. 6 b.

As used herein, the term “angled” refers to a microstructure that is notperpendicular to the base. The angle of a microstructure in relation tothe base can be understood with reference to FIG. 5a , which illustratesa straight microstructure having a line, through the body, connectingthe tip to a center point. The “center point” is the center of thefoundation. The angle (“center point angle”; θ_(c)) formed between theline and the base defines the angle of the entire microstructure.

For microstructures, if the tip is not directly above the center pointthen the microstructure is angled.

Curved microstructures may be defined by an angle if a tip-to-centerpoint line can be drawn so as to define an angle in relation to thebase. However, extensively curved microstructures may not allow astraight line to be drawn through the body from the tip to the centerpoint.

As used herein, the term “microneedle” is intended to refer to anymicrostructure comprising straight or tapered shafts. In one embodiment,the diameter of the microneedle is greatest at the base end of themicroneedle and tapers to a point at the end distal the base. Themicroneedle can also be fabricated to have a shaft that includes both astraight (untapered) portion and a tapered portion. The microneedles canbe formed with shafts that have a circular cross-section in theperpendicular, or the cross-section can be non-circular. For example,the cross-section of the microneedle can be polygonal (e.g. star-shaped,square, rectangular, and triangular), oblong, or another shape. The tipportion of the microneedles can have a variety of configurations. Thetips can be symmetrical or asymmetrical about the longitudinal axis ofthe microneedle shaft. In one embodiment, the tips are beveled. Inanother embodiment, the tip portion is tapered. In one embodiment, thetapered tip portion is in the shape of a pyramid on a shaft portionhaving a square cross-section, such that the microneedle is in the shapeof an obelisk. Of course, the tip and/or shaft can be rounded, or haveanother shape, as well. In some embodiments the microneedles comprise ashape that is a e.g., rod, cone, square, rectangle, pyramid, cylinder.

As used herein, the term “microblade” is intended to refer to aneedle-like microstructure comprising a tip that is not a point, but isinstead a blade. This embodiment is illustrated, for example, in FIGS.8a -1 to 8 a-6 and 12 b, which shows a picture of a microstructure arraycomprising microblades. The tip portion of these structures is wide in afirst dimension (50 μm in this picture) and very narrow in a seconddimension, with respect to the first dimension (e.g., less than 10 μm inthia picture) Furthermore, in some embodiments, the thickness at the tipis smaller than the width of the microblades near their base.

As used herein, the term “microanchor” is intended to refer to anymicrostructure capable of anchoring a device according to the presentdisclosure to skin or tissue. Examples of microanchors includemicrostructures with ends shaped like hooks or barbs. As used herein,the term “barb” refers to a tip configuration comprising angled portionsprojecting away from the tip in order to secure the barb within thepenetrated skin or tissue.

As used herein, the term “microfishscale” is intended to refer to anymicrostructure comprising a scale that partially overlaps, with otherscales of microscale dimensions and mimics the scale of a fish.

As used herein, the term. “micropillar” is intended to refer to anymicrostructure comprising a cylindrical shape.

As used herein, the term “microhair” is intended to refer to anymicrostructure comprising hair-like features which enable the contactingand sticking of the microhair to another object via van der Waalsforces.

The term “tapered” is meant to describe a microstructure wherein thewidth or diameter gradually diminishes along the length of the needlefrom the base to the tip, such that the base comprises the largest widthor diameter, and the tip comprises the smallest width or diameter. A“partially tapered” microstructure is one in which a portion of themicrostructure is tapered and a portion of the microstructure is nottapered. For example, but not to be limited, such a microstructure cancomprise a tapered portion extending from a block shaped base; or e.g.,a cylindrical base portion can extend toward the tip for a certainlength, and then a tapered portion can continue to the tip.Alternatively, the microstructure can comprise a tapered portionextending from the base, with a non-tapered portion being at the tip endof the microstructure.

The term “stretchable” as used herein is meant to encompass any materialthat can be elongated in any direction, e.g., as a result of a pullingforce. “Stretchable” encompasses the term “elastic” and thus an objectthat is said to be stretchable should be understood to optionallycomprise elasticity. Thus in some embodiments, if an object is said tobe stretched, this is meant to include at least two embodiments; thefirst being that the stretching force will be counteracted by aretractile force, and thus once the stretching force is removed, theobject will inherently attempt to retract (e.g., as is the case with anelastic object). The second embodiment is one in which the object doesnot inherently comprise elasticity, and thus no such retractile force isinherent.

The term “flexible” is meant to describe any material that is capable ofsustaining a bending force without being damaged. In some embodiments, a“flexible” material comprises enough flexibility as to allow the deviceof the present invention to bend so as to fit the contours of thebiological barrier, such as, e.g., the skin, vessel walls, or the eye,to which the device is applied.

The term “backing” as used herein is meant to describe an optionalcomponent of the present wound closure devices which is attached to oneor more arrays. In some embodiments the backing attaches two or moremicrostructure arrays together. As is thoroughly described in thedetailed description, the backing may comprise any suitable material,and in several embodiments it is flexible, stretchable, elastic, orcombinations thereof.

The term “cover” as used herein in meant to describe an optionalcomponent of the wound closure systems disclosed herein whereby itcovers the wound. After application of the wound closure devices of thepresent invention, such a cover may be optionally applied over and/orattached to the top of the device. e.g., assist in securing the devicein place. The covers may be made of any suitable material, as isdiscussed and defined thoroughly in the detailed description sectionbelow. In some embodiments the covers comprise adhesive.

When it is said that one or more microstructures are “affixed to abacking” it is meant that the microstructures may optionally be eitherdirectly affixed to the backing, or indirectly affixed to the backing(e.g., in some embodiments, “affixed to a backing” is meant to encompassthe scenario wherein the microstructures are fashioned on, or affixedto, a base, said base being affixed to a backing). Accordingly, thephrase “one or more microstructures affixed to a backing” canappropriately be used interchangeably with the phrase “a backingcomprising one or more microstructures.”

As used herein, the term “pitch” is meant to describe the distancebetween the tips of two or more adjacent microstructures in a givenarray, or in two or more separate arrays. In some embodiments the pitchranges from 30 μm to 1 cm or more.

Accordingly, certain embodiments provide for microstructure arrays asdisclosed herein, wherein the microstructures are separated from oneanother with a pitch of 30 μm, 50 μm, 70 μm, 90 μm, 100 μm, 150 μm, 200μm, 250 μm, 300 μm, 350 μm, 400 μm, 450 μm, 500 μm, 550 μm, 600 μm, 650μm, 700 μm, 750 μm, 800 μm, 850 μm, 900 μm, 950 μm, 1 mm, 1.1 mm, 1.2mm, 13 mm, 14 mm, 1.5 mm, 2 mm, 2.5 mm, 3 mm, 3.5 mm, 4 mm, 4.5 mm, 5mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, or more, including all decimals(e.g., 3.1 mm, 3.2 mm, 3.3 mm, etc.) and ranges (e.g., 1-10 mm, 5-10 mm,7-10 mm, etc.) in between, of the microstructure array pitches set forthherein. The pitch may be constant throughout an array, e.g., an equaldistance separates all microstructure tips from one another in a givenarray; or the pitch may vary.

Reference herein to the term “tape” or “microstructure tape” or“microstructure array tape” is simply meant to describe anadhesive-comprising microstructure array roll bandage, as describedherein.

Reference to a “Draize score” refers to a score according to the Draizescale, which is a standard scoring system used to measure skintoxicities of devices and drugs.

As used herein, the term “adhesive” or “glue” are used interchangeably.These terms are meant to have their ordinary meaning, e.g., anysubstance that is capable of binding two or more materials together. Insome embodiments, the adhesive is intended to be used on the skin. Insuch embodiments the adhesive may be a medical grade adhesive such as,e.g., an acrylate (such as, e.g., are used on the Steri-Strips orSteri-Strip S isthmus), or hydrogel based adhesives that can stick towet surfaces (e.g. Polyethylene glycol (PEG) hydrogel). In otherembodiments the adhesive component comprises nanostructures that provideglueless adhesion.

The term “applicator” as used herein is meant to describe any machine orinstrument that is used to affix a wound closure device, e.g., to theskin or tissue surrounding a wound. Accordingly, the use of medicalinstruments such as forceps, tweezers, clamps, pins, etc., to apply sucha device would be considered to be use of an applicator. The term“applicator” also refers to the roll on hand held dispenser disclosedherein. Thus, when it is said that the device is applied without anapplicator, this is to be understood as being applied by human hand,without the aid of a machine or instrument.

Microstructures

The microstructures comprised in the wound closure devices disclosedherein may be made of any material or mixture of materials. In someembodiments, the material is a natural material, or a mixture of naturalmaterials: while in other embodiments it is a synthetic material, or amixture of synthetic materials. In some embodiments, the microstructuresare comprised of nontoxic, biodegradable, bioresorbable, orbiocompatible materials, or combinations thereof; and in otherembodiments they are not. Still other embodiments provide formicrostructures, according to the present disclosure, comprisingmixtures of one or more synthetic materials and one or more naturalmaterials. In particular embodiments, microstructures are made of amaterial selected from a polymer, a metal, a biomaterial, and acombination thereof.

In certain embodiments, microstructures of the present invention arecomprised of a material selected from the group consisting of PMMA,silicone, chitin, chiosan, ecoflex, titanium, glass, metal, steel,silicon, silk, catgut, chromic catgut, polyglycolic acid, polydioxanone,polytrimethylene, carbonate, nylon, polypropylene, polyester,polybutester, poly(lactic-co-glycolic acid), polylactone, elastin,resilin, collagen, cellulose, and any combination thereof.

Embodiments of the present invention provide for microstructuresselected from the group consisting of microneedles, microblades,microanchors, microfishscale, micropillars, microhairs, and combinationsthereof. Microstructures may be designed to be able to penetrate intoskin or tissue, or they may be designed to merely grasp skin or tissuewithout actual penetration. In some embodiments, the microstructures aredesigned to penetrate the skin or tissue to specific depths, e.g.,through the epidermal or dermal layers, or to the various sublayersthereof.

The wound closure devices of the present invention may comprisemicrostructures of any desired size, dimension, and geometry.Additionally, microstructures may optionally comprise surfaces which aresubstantially smooth, or which comprise uneven surfaces, e.g., amicrostructure comprising sides which are wavy, or which compriseprotrusions, indentations, or depressions.

In one aspect, the microstructure includes a foundation adjacent to abase, a tip, and a body connecting the foundation to the tip.

In one embodiment, a line extending from the tip perpendicular to thebase does not pass through the foundation. Angled and/or curvedmicrostructures may have a shape that positions the tip beyond thefoundation. Examples of such microstructures are illustratedschematically in Figure a and photographically in FIG. 2b .Additionally, it will be appreciated that any microstructure, no matterthe body shape, angle, and/or curvature, that has a tip position asdescribed is contemplated by the present embodiment.

In one embodiment, a line extending from the tip perpendicular to thebase passes through the foundation. Angled and/or curved microstructuresmay have a shape that positions the tip within the perimeter of thefoundation. Examples of this microstructure configuration areillustrated schematically in FIG. 5b and photographically in FIG. 2a .Additionally, it will be appreciated that any microstructure, no matterthe body shape, angle, and/or curvature, that has a tip position asdescribed is contemplated by the present embodiment.

In one embodiment, an angle between the body and the base is a constantangle. In such an embodiment, the center point angle and the face angleare constant. FIGS. 5a and 6a are examples of such a microstructure.

In one embodiment, two or more different angles are formed between thebody and the base between the foundation and the tip. Curved orarticulated microstructures are examples of such a microstructure. FIGS.6b and 6c are examples of such a microstructure.

The body of the microstructures can have concave surfaces, convexsurfaces, and a combination of concave and convex surfaces. In oneembodiment, the body comprises at least one concave surface. In oneembodiment, the body comprises at least one convex surface. In oneembodiment, the body comprises at least one concave surface and at leastone convex surface.

In certain embodiments, the microstructures comprise microneedles.Microneedles narrow from a foundation to a tip. Representativemicroneedles are illustrated in FIGS. 3a -1 to 3 a-6.

Referring to FIG. 3a -4, each microneedle includes a foundation that hasa width (W1) and thickness (T). While the microneedles illustrated inFIGS. 3a -1 to 3 a-6 have rectangular foundations, it will beappreciated that this is only one embodiment of the microneedles. Otherembodiments include microneedle foundations that are circular, oval,triangular, square, higher-order polygons, and combinations thereof.

The tip of the microneedle extends a length (L) from the foundation. Thetip can also be offset a distance (D) such that the tip is not centeredvertically above the foundation. In certain embodiments, the tip iscentered vertically above the center point of the foundation. In otherembodiments, the tip is positioned vertically above a point on theperimeter of the foundation.

While the tip of a microneedle converges to a single point, the tip hassome diameter as a result of fabrication.

As illustrated in FIG. 3a -6, each microneedle has a face angle (OF)formed between a side wall of the microneedle and the surface supportingthe microneedle.

In certain embodiments, the microstructures comprise microblades.Microblades narrow from a foundation to a tip. Representativemicroblades are illustrated in FIGS. 8a -1 to 3 a-6.

Referring to FIG. 8a -4, each microblade includes a foundation that hasa width (W1) and thickness (T). While the microblades illustrated inFIGS. 3a -1 to 3 a-6 have rectangular foundations, it will beappreciated that this is only one embodiment of the microblades. Otherembodiments include microblade foundations that are circular, oval,triangular, square, higher-order polygons, and combinations thereof.

The tip of the microblade extends a length (L) from the foundation. Thetip can also be offset a distance (D) such that the tip is not centeredvertically above the foundation. In certain embodiments, the tip iscentered vertically above the center point of the foundation. In otherembodiments, the tip is positioned vertically above a point on theperimeter of the foundation.

Unlike a microneedle, a microblade has a tip that forms a line, not asingle point. The microblade tip has a width (W2) and a nominalthickness.

As illustrated in FIG. 8a -6, each microblade has a face angle formedbetween a side wall of the microblade and the surface supporting themicroblade.

Microneedles and microblades interact with the skin of a patient indifferent ways, given their different characteristics. For example,microblades provide more surface area than microneedles of the samelength and width. By providing a larger surface area, microblades areable to remain anchored to the skin with higher lateral tension thanmicroneedles. Consequently, a smaller number of microblades can be usedto close a wound under tension than can be achieved with microneedles.

Microstructures may have heights ranging from approximately 1 μm toapproximately 3 mm. Thus microstructures may have heights ofapproximately 1 μm, m, 50 μm, 100 μm, 150 μm, 200 μm, 250 μm, 300 μm,350 μm, 400 μm, 450 μm, 500 μm, 550 μm, 600 μm, 650 μm, 700 μm, 750 μm,800 μm, 850 μm, 900 μm, 950 μm, 1 mm, 1.5 mm, 2 mm, 3 mm, or higher,including all integers (e.g., 2 μm, 3 μm 4 μm, etc.) and ranges (e.g.,100-1000 μm, 500-1000 μm, 700-1000 μm, 950-1000 μm, etc.) in between, ofthe microstructure heights set forth herein. Accordingly, themicrostructure arrays of the present invention may comprise individualmicrostructures that have heights of approximately 1 μm up toapproximately 3 mm, as described above. Longer (e.g., 3 mm or longer)microstructures are needed for treatment areas that include thickerdermal tissue (e.g., the back).

Microstructures may have widths or diameters, as measured by the areameeting the foundation of the base, ranging from approximately 15 μm upto approximately 2 mm (e.g., see Width ‘W1’ in FIGS. 8a -4). Thus,microstructures may have widths or diameters of approximately 15 μm, 30μm, 50 μm, 100 μm, 150 μm, 200 μm, 250 μm, 300 μm, 350 μm, 400 μm, 450μm, 500 μm, 550 μm, 600 μm, 650 μm, 700 μm, 750 μm, 800 μm, 850 μm, 900μm, 950 μm, 1 mm, 1.5 mm, 2 mm, or wider, including all integers (e.g.,101 μm, 102 μm, 103 μm, etc) and ranges (e.g., 100-1000 μm, 200-500 μm,500-1000 μm, 700-1000 μm etc.) in between, of the microstructure widthsand diameters set forth herein. Accordingly, the microstructure arraysof the present invention may comprise individual microstructures thathave widths or diameters of at least or approximately 15 μm up toapproximately 2 mm, as described above.

Microstructures may have tips with widths or diameters of approximately10 nm up to approximately 50 μm (e.g., see Width ‘W2’ in FIGS. 8a -4).Thus, microstructures may have tips with a width or diameter ofapproximately 10 nm, 20 nm, 30 nm, 40 nm, 50 nm, 60 nm, 70 nm, 80 nm, 90nm, 100 nm, 125 nm, 150 nm, 175 nm, 200 nm, 300 nm, 400 nm, 500 nm, 600nm, 700 nm, 800 nm, 900 nm, 1 μm, 5 μm, 10 μm, 15 μm, 20 μm, 25 μm, 30μm, 35 μm, 40 μm, 45 μm, 50 μm, or wider, including all integers (e.g.,11 nm, 12 nm, 13 nm, etc.) and ranges (e.g., 10 m-50 μm, 200-1000 μm,500-1000 μm, 700-1000 μm, etc.) in between, of the microstructure widthsor diameters set forth. Accordingly, the microstructure arrays of thepresent invention may comprise individual microstructures that have tipswith widths or diameters of approximately 10 nm up to approximately 50μm, as described above.

If a microstructure includes a tip offset (D), the offset can be from 1nm to one-half the thickness (T) or width (W1) of the foundation of themicrostructure. In one embodiment, the tip offset is from 20% to 33% ofthe thickness of the foundation of the microstructure.

Microstructure Bases

Bases, which may optionally comprise the various microstructures andmicrostructure arrays, may be made of any suitable material. The basemay be transparent or substantially transparent (e.g., to enablenon-invasive wound observation) or alternatively, it is not transparent(e.g., to hide the wound). The base may optionally comprise nontoxic,biodegradable, bioresorbable, or biocompatible materials, orcombinations thereof. The base may be made out of the same material asthe microstructures it comprises, or it may be made of a differentmaterial.

Accordingly, as is the case with the microstructures, the presentinvention provides for microstructure bases comprising any material ormixture of materials. In some embodiments, the material is a naturalmaterial, or a mixture of natural materials; while in other embodimentsit is a synthetic material, or a mixture of synthetic materials. Stillother embodiments provide for microstructure bases, according to thepresent disclosure, comprising mixtures of one or more syntheticmaterials and one or more natural materials. In particular embodiments,microstructure bases are made of a material selected from a polymer, ametal, a biomaterial, a hydrogel, a glass, and a combination thereof.

In certain embodiments, microstructure bases of the present inventionare comprised of a material selected from the group consisting of PMMA,silicone, chitin, chitosan, titanium, glass, metal, steel, silicon,silk, catgut, chromic catgut, polyglycolic acid, polydioxanone,polytrimethylene carbonate, nylon, polypropylene, polyester,polybutester, poly(lactic-co-glycolic acid), elastin, resilin, collagen,cellulose, and any combination thereof.

In one certain embodiment, the microstructures and the bases are bothcomprised of PMMA. In another certain embodiment, the microstructuresand the bases are both comprised of silicone.

The thickness of the base may be substantially uniform throughout thedevice, or alternatively it may be varied. In some embodiments, thethickness of the base is determined by the material that it is made outof, e.g., a 1 mm thickness for a silicone base may be used, as thismaterial comprises acceptable flexibility at such a thickness; a basecomprising PMMA, on the other hand may be fashioned at approximately 125μm or less thick in some instances, so as to maintain some degree offlexibility. Alternatively, a PMMA base may be thicker, e.g., 300 μmthick, if a stiffer base is desired. One skilled in the art can easilydetermine the appropriate thickness of a base depending on the materialfrom which it is made, and the desired flexibility or lack thereof ofthe base. Accordingly, in some embodiments, the thickness of the baseranges from approximately 10 μm to approximately 1 mm. In particularembodiments, the base thickness is approximately 10 μm, 20 μm, 30 μm, 40μm, 50 μm, 60 μm, 70 μm, 80 μm, 90 μm, 100 μm, 125 μm, 150 μm, 175 μm,200 μm, 300 μm, 400 μm, 500 μm, 600 μm, 700 μm, 800 μm, 900 μm, 1 mm orthicker, including all integers (e.g., 126 μm, 127 μm 128 μm, etc.) andranges (e.g., 501 μm-200 μm, 100-160 μm, 120-140 μm, etc.) in between,of the microstructure base thicknesses set forth.

Bases may be as long or wide as is necessary to comprise the desiredmicrostructure array or arrays. For example, but not to be limited inany way, the dimension of a base may be as small as 1 mm wide in thedimension perpendicular to the wound, so as to have one set ofmicrostructures parallel to the wound; and this dimension may range aswide as 10 cm or larger. For the dimension parallel to wound the basescan range from 2 mm, to as large as 50 cm long or more (e.g., as isoptionally the case in some of the microstructure array roll bandagesdisclosed herein). Accordingly, base lengths may range fromapproximately 2 mm, 5 mm, 10 mm, 2 cm, 3 cm, 4 cm, 5 cm, 10 cm, 20 cm,30 cm, 40 cm, 50 cm, or longer, including all integers (e.g., 11 mm, 12mm, 13 nm, etc.) and ranges (e.g., 2 mm-50 cm, 5 mm-15 mm, 5 mm-10 mm,etc.) in between, of the base lengths parallel to the wound set forth;and base widths may range from approximately 1 mm, 3 mm, 5 mm, 7 mm, 9mm, 1 cm, 2 cm, 3 cm, 4 cm, 5 cm, 10 cm, or longer, including allintegers (e.g., 11 mm, 12 mm, 13 mm, etc.) and ranges (e.g., 1 mm-10 cm,2 mm-10 mm, 5 mm-0 mm, etc.) in between, of the base lengthsperpendicular to the wound set forth, as described herein.

Angled Microstructures

In some embodiments, the wound closure devices of the present inventioncomprise microstructures at an angle relative to the backing or base.The microstructures may be positioned at any suitable angle. In someembodiments they are affixed at an angle relative to a backing or base,wherein the angle is approximately 15, 30, 45, 60, 73, or 90 degrees,including all integers (e.g., 16°, 17°, 18°, etc.) and ranges (e.g.,15°-90°, 30°-90°, 45°-70°, etc.) in between, of the angles set forth. Inone embodiment, the microstructures are at an angle of greater than 50degrees relative to the backing or base. In one embodiment, themicrostructures are at an angle of from 45 to 70 degrees relative to thebacking or base. In one embodiment, the microstructures are at an angleof from 50 to 70 degrees relative to the backing or base.

In some embodiments, the wound closure devices of the present inventionalso include microstructures with an angle relative to the backing orbase that is variable depending on its position in any microstructurearray. In certain embodiments, the angle of one or more microstructuresis approximately constant along the entire length of the microstructure,and in other embodiments, the angle of the microstructure varies alongthe length of the microstructure.

Microstructures may be angled in any direction. In some embodiments, allmicrostructures in a particular array are angled in the same direction,or in approximately the same direction; while in other embodiments theyare not. In certain embodiments, microstructures on a device are angledtowards a wound. In some particular embodiments, the microstructures inan array comprise subsets of microstructures angled in differentdirections.

Microstructure Arrays

The wound closure devices of the present invention may comprisemicrostructure arrays patterned on one or more bases in a variety ofshape and dimensions. FIGS. 3a -1 to 3 a-6 and 8 a-1 to 8 a-6 showschematic designs of several arrays we have produced. The details ofexemplary microneedles (FIG. 3b ) and microblades (FIG. 8b ) areprovided in a table. Furthermore, photographs of one such microneedlearray and microblade arrays are provided in FIGS. 7a and 7b , and FIGS.12a and 12b , respectively.

In particular, devices of the present invention may comprise arrays inwhich the length or width of an array is designed to enable treatment ofspecific wound types or sizes. For example, but not to be limited in anyway, the dimension of an array that runs parallel to a wound can be aswide as 50 cm e.g., to treat a 50 cm long straight wound; or,alternatively it can be as narrow 2 mm wide, e.g., to treat a 2 to 5 mmlong wound. Similarly, the length of the other dimension of an array(i.e., the dimension that runs perpendicular to the wound) may be assmall as 1 mm and as large as 50 mm. Accordingly, the dimensions of anindividual array may comprise lengths and/or widths of 1 mm, or they maycomprise lengths and/or widths of 2 mm, 3 mm, 5 mm, 7 mm, 9 mm, 10 mm, 2cm, 3 cm, 4 cm, 5 cm, 10 cm, 15 cm, 25 cm, 50 cm, or more, including allintegers (e.g., 11 cm, 12 cm, 13 cm, etc.) and ranges (e.g., 3 mm-50 cm,9 mm-5 cm, 1 cm-50 cm, etc.) in between, of the microstructure arraylengths and widths set forth.

The microstructure arrays may comprise any appropriate number ofmicrostructures. In some embodiments, the number of microstructurescomprised in an individual array varies from 1 microstructure per array,to more than 1000 microstructures per array. The microstructure arraysmay comprise any density of microstructures. In some embodiments, thedensity of microstructures comprised in an individual array varies from1 microstructure per cm², to 1000 microstructures per cm². In oneembodiment, the density of microstructures comprised in an individualarray is from 1 to 100 per cm². In one embodiment, the density ofmicrostructures comprised in an individual array is from 5 to 50 percm². In one embodiment, the density of microstructures comprised in anindividual array is from 10 to 20 per cm². In one embodiment, thedensity of microstructures comprised in an individual array is from 5 to10 per cm².

In particular embodiments, the density of microstructures in an array isdecreased to reduce or eliminate the induction of an inflammatoryresponse to the wound closure device. Without being limited by theory,data suggest that arrays comprising lower densities of microstructures(e.g., see FIG. 7a and FIG. 12a ) induce less (or no) inflammation thanarrays with higher microstructure densities (e.g., see Example 3).

In various embodiments, the microstructure arrays of the presentinvention comprise microstructures patterned in a variety of shapes orpatterns. Any shape or pattern of microstructure arrays is within thescope of the present invention, in some embodiments, the arraypatterning comprises straight edges. In some embodiments, the arrays arepatterned with rounded edges. In still further embodiments, the arraypatterning comprises shapes with both rounded and straight edges. Insome certain embodiments, arrays are patterned in a shape selected fromthe group consisting of oval, diamond, pyramid, and circle. In somecertain embodiments, arrays are patterned in a rectangular shape. Insome certain embodiments, arrays are patterned in the shape of a square.In some embodiments, arrays comprise pluralities of microstructures thatare pattern into separate shapes, wherein two or more regions of thearray comprise a higher density of microstructures than the otherregions of the array. Take for example, but not to be limited in anyway, a single square shaped array, which may in one embodiment comprisee.g., groups of microstructures in any locale, such as, one group ineach of the corners of the array, wherein the four microstructure groupsare separated by a region of the array that does not comprise anymicrostructures, or optionally comprises microstructures at a differentdensity than the density of the microstructures comprised in one of thegroups.

Another non-limiting example of this concept is, e.g., a wound closuredevice that is made up of a single base comprising a singlemicrostructure array, wherein the base comprises a shape that is similaras the device shown in FIGS. 15a to 15e . Such abase comprises group ofmicrostructures on one end of the device and another group on the otherend of the device, such that the groups separated by a space that doesnot comprise any microstructures.

In some embodiments, the individual microstructures are distributeduniformly throughout an individual array, and in other embodiments themicrostructures are not distributed evenly throughout an array. Incertain embodiments, wherein the devices comprise a plurality of arrays,distribution of the individual microstructures may be constant betweendifferent arrays (e.g., all arrays comprising uniformly distributedmicrostructures), or they may be varied between arrays (e.g., somearrays comprising uniformly distributed microstructures), and otherarrays comprising microstructures distributed in a non-uniform manner.

In some embodiments, the size, dimension, and geometry of themicrostructures are constant throughout an individual array, while inother embodiments these properties are varied, e.g., anisotropically.Additionally, in certain embodiments wherein the devices comprise aplurality of arrays, these physical properties may be constant betweendifferent arrays (e.g., all arrays comprising identical designs), orthey may be varied (e.g., different arrays optionally comprisingdifferent designs). Accordingly, some embodiments provide for woundclosure devices comprising arrays that are homogeneous with regard tothe microstructures they comprise; while other embodiments provide forwound closure devices comprising arrays that are heterogeneous withregard to the microstructures they comprise.

In some embodiments, the devices comprise two different microstructurearrays, said arrays comprising angled microstructures; wherein themicrostructures from one array are angled toward the microstructures ofthe other array, and vice versa. In such embodiments, an isthmus mayseparate the two different microstructure arrays, such that the arraysare angled towards a wound onto which the device is applied (e.g., ifthe isthmus is positioned above the wound).

Optionally, the angles of the opposing microstructures comprised in theseparate arrays may be the same (e.g., both arrays comprisingmicrostructures that are angled towards the microstructures of the otherarray at e.g., approximately 45°), substantially the same, or they maybe different. Similarly, another embodiment provides for a wound closuredevice comprising more than two microstructure arrays, wherein at leasttwo of said arrays are angled towards one another as described above. Insome embodiments, opposing arrays that are angled towards each other maybe located in the same array region (i.e., they are not separated by anisthmus). In some embodiments, opposing arrays that are angled towardseach other may be located in different array regions (i.e., they areseparated by an isthmus).

The arrays have an aspect ratio defined in relation to the position onthe device to be positioned above a wound (e.g., the isthmus). Thelength is defined as the dimension of the array extendingperpendicularly away from the wound. The width is defined as thedimension of the array extending parallel to the wound, in oneembodiment the aspect ratio of the array is from 0.1 to 10. In oneembodiment the aspect ratio of the array is from 0.4 to 3. In oneembodiment the aspect ratio of the array is from 1 to 5. In oneembodiment the aspect ratio of the array is from 2 to 3.

Microstructure Manufacture

The microstructures comprised in the wound closure devices disclosedherein may be manufactured using any method available to the skilledartisan. In some embodiments, the microstructures are made bymicrofabrication processes that are based on established methods e.g.,those used to make integrated circuits, electronic packages and othermicroelectronic devices, augmented by additional methods used in thefield of micromachining and micromolding.

Arrays of microstructures can be fabricated, e.g., using combinations ofreplica molding; injection molding; microlithography; die cutting andetching: cutting; laser cutting; etching such as have been described,e.g., in WO2007127976A2; WO2002072199A2; WO2002064193A2; U.S. Pat. Nos.6,503,231 and 6,334,856, WO1999064580 and WO2000074763; WO2012167162,all of which are incorporated herein by reference. For example, but notto be limited, microstructures can be fabricated by (i) etching themicrostructure directly, (ii) etching a mold and then filling the moldwith a melt or solution comprising the microstructure material to formthe microstructure product, or (iii) etching a microstructure master,using the master to make a mold, and then filling the mold to form themicrostructure replica (of the master). In some particular embodiments,the microstructures are manufactured according to the technique outlinedin FIGS. 1a to 1f and described in Example 1. Briefly, a master of thedesired dimensions is made with a metal, silicon, or a polymer viamicromachining, microlithography, etching, laser cutting, or acombination thereof. The master is replicated using a polymericmaterial—e.g., silicone. The silicone is then lifted out of the masterand is filled with a solution or a melt of the microneedle material, thefilling may occur by e.g., drop casting or spraying. After curing ordrying of the solution or melt the microneedles are lifted out from themold.

Backing

Embodiments of the present invention relate to wound closure devicescomprising one or more of a variety of microstructures, saidmicrostructures optionally being affixed to a backing. Accordingly, insome embodiments, one or more microstructure arrays are affixed to abacking, said microstructures optionally comprising a variety of sizes,dimensions, and geometries. Any suitably backing may be used in thefabrication of the present devices, and in some embodiments the backingis optionally flexible and/or stretchable. The backing is a separatecomponent, upon which the microstructures are affixed, e.g., viaattachment of a base that comprises one or more microstructures, or viadirect attachment of one or more individual microstructures onto thebacking. Such a base typically comprises two substantially planarsurfaces, i.e., an upper surface and a lower surface; wherein one ormore microstructures protrude perpendicularly or at an angle from theupper of said surfaces, and the lower of said surfaces is substantiallyflat. In such an instance, the backing may be affixed to the lowersurface by any suitable means, e.g., by gluing.

Accordingly, the wound closure devices of the present invention may beprovided with or without a backing attached. For example, the devices ofthe present invention may be provided in a ready to use form, whereinone or more microstructure arrays are affixed to a backing according tothe present disclosure. Furthermore, some of the wound closure devicesof the present invention do not comprise a backing, but instead compriseone or more microstructures or microstructure arrays on a suitable base,e.g., a base comprising flexibility, stretchability, or flexibility andstretchability, such that the device can perform its intended functionon its own. Alternatively, it is also contemplated that a wound closuredevice according to the present invention may be packaged for commercialuse with one or more suitable unattached backings, said backingsoptionally comprising different shapes, sizes, or compositions, suchthat one or more appropriately sized backings may be selectedspecifically to treat a certain type of wound. One or moremicrostructure arrays, provided in such a package, may then be attachedto the backing as needed, to generate a wound specific device.Accordingly, such a device may optionally come with one or moreattachment means, such as, e.g., an adhesive; wherein the attachmentmeans may optionally be comprised on one or more components of thedevice, or it may be provided separately, e.g., in a package orcontainer.

Suitable backing for use in the present devices include those which aretransparent, or substantially transparent, thus allowing fornon-invasive monitoring of wound healing, as well as backings that arenot transparent. In some embodiments, backings are in the form ofsheets; bandages; rolls; films; cloths; woven materials; or otherpermeable, semi-permeable, or impermeable coverings. The backings may bemade from natural, synthetic, and/or artificial materials; and in someparticular embodiments, they comprise a polymeric substance (e.g., asilicone, a polyurethane, or a polyethylene). The backing may comprisedof materials that are nontoxic, biodegradable, bioresorbable, orbiocompatible. In some embodiments, the backing comprises inertmaterials, and in other embodiments, the backing comprises activatedmaterials, (e.g., activated carbon cloth to remove microbes, asdisclosed in WO2013028966A2).

In some embodiments, the backing further comprises elastic properties,wherein the elasticity may optionally be similar throughout the device,or it may be varied along or across the device. Accordingly, in someembodiments, the backing comprises a material singularly, or incombination, selected from the group consisting of medical tape, whitecloth tape, surgical tape, tan cloth medical tape, silk surgical tape,clear tape, hypoallergenic tape, silicone, elastic silicone,polyurethane, elastic polyurethane, polyethylene, elastic polyethylene,rubber, latex, Gore-Tex, plastic and plastic components, polymers,biopolymers, and natural materials.

In some certain embodiments, the present invention comprises a woundclosure device, as disclosed herein, comprising one or moremicrostructures affixed to a commercially available backing selectedfrom the group consisting of 3M Transpore Surgical Tape, 3M BlendermSurgical Tape, Coverlet Fabric, Dynarex Silk Surgical Tape, Kendall™Hypoallergenic Clear Tape, Tenderfix™ Hypoallergenic Cloth Tape,Curasilk™ Cloth Tape, Curapont, Leukosan Skinlink, Leukosan Strip,Leukostrip, Steri-Strip, Steri-Strip S, Urgo strip, and combinationsthereof

Devices

The wound closure devices of the present invention comprise one or moremicrostructures as described herein. The devices may have any suitableor desirable shape, size, or configuration. For example, devices of thepresent invention may in some embodiments have singularly, or incombination, a square, rectangular, round, oval, butterflied, or othershape; and in some embodiments, they may include sheets, tapes, rolls,or covers that can be cut or wrapped around, for example, a portion of alimb, to cover a wound on the limb.

In some instances the devices comprise generic features, according tothe present specification, that enable the closure of a wide variety ofwounds.

In certain embodiments, the devices comprise microstructures 700 micronsto 1 mm in length.

In certain embodiments, the devices comprise microstructures that are200 microns to 400 microns in width.

In certain embodiments, the devices comprise microstructures at anglesof degrees to 60 degrees.

In certain embodiments, the devices comprise arrays with a density of 10to 100 microstructures per cm².

In some instances, components of the various device are designed,accordingly to the specifications disclosed herein, to specificallyoptimize a device for treating a particular wound, tissue type, orlocation of the body. Accordingly, various specifications. e.g., themicrostructure type, geometry, size, specifications, spacing within anarray, array structure, number of arrays, location of arrays, dimensionof arrays, isthmus, materials of the various components, etc., may insome instances be carefully chosen to design a wound closure devicee.g., to treat a specific type of wound, or for treatment of any woundlocated on a particular type of tissue or location on the patient. Forexample, but not to be limited in any way, treatment of wounds on thepalm or back may need longer needles than would be required to treat awound on the face, due to the inherent variety of skin thickness thatexists in these (and other) different sites of the body. In addition,the treatment of wounds may require shorter needles in patients, who areelderly or have chronic medical conditions or skin conditions, orpatients treated with drugs, such as steroids, that are known to resultin thinning of the skin. As such, the wound closure devices may compriseany suitable shape and size to adequately cover a variety of wounds,Additionally, the devices may be of any length or width suitable tocover a single wound, or optionally a plurality of wounds (such as e.g.,a tape bandage).

The devices have an aspect ratio defined in relation to the position onthe device to be positioned above a wound (e.g., the isthmus). Thelength is defined as the dimension of the device extendingperpendicularly away from the wound. The width is defined as thedimension of the device extending parallel to the wound. In oneembodiment the aspect ratio of the device is from 0.1 to 10. In oneembodiment the aspect ratio of the device is from 0.4 to 3. In oneembodiment the aspect ratio of the device is from 1 to 5. In oneembodiment the aspect ratio of the device is from 2 to 3.

Wound closure devices are removed when the wound is closed and showssufficient healing. This varies for different body sites, such thatsutures and other devices are removed 3-5 days, 6-10, and 11-14 days onthe head (including face and neck), extremities, and trunk,respectively. Unexpectedly, it has been determined that the woundclosure microneedle prototype devices led to accelerated healing ofwounds compared to closure of wounds with sutures. See Example 5. Morerapid closure of healing is beneficial to patients because it decreasesthe risks of infection, wound dehiscence, and other adverse events, andalso enables patients to return to activities of daily living at anearlier time. In addition, accelerated healing is of benefit to patientswith chronic medical conditions or skin conditions, or patients treatedwith drugs, such as steroids, that are associated with delayed healingof wounds.

To avoid infection, it is beneficial that the wound closure devices ofthe present invention be sterile prior to application to the skin ortissue. Accordingly, in one embodiment, the wound closure devices aresterile when packaged. In another embodiment, the wound closure devicesare sterilized immediately prior to use. Many suitable means ofsterilization are known and common in the art, and any such means issuitable for sterilizing the wound closure devices, provided saidsterilization does not destroy the device. Such means may include, butare not limited to sterilization by heat, radiation, or chemical agents.

Furthermore, a plurality of wound closure devices, as described herein,may be connected to one another such that more than one of the devicescan be applied to a wound at the same time. Such a connection may be atany suitable location on the device, and will of course vary dependingon shape and intended use of the particular device. A non-limitingexample of such an arrangement includes, e.g., a plurality ofrectangular-shaped devices connected together via one or both sides thatrun perpendicular to the wound; such that a plurality of connected woundclosure devices may be applied simultaneously in parallel, wherein eachdevice is situated perpendicular to the wound, and the plurality ofdevices extends along the longitudinal axis of the wound like railroadties along a track.

The devices of the present invention may optionally comprise adhesivesto assist in the application of the device, and/or to help maintain thedevice in the position that it is applied to. Furthermore, the devicesmay comprise adhesive which binds a microstructure array to a backinge.g., via the direct binding of a base portion to a backing, as isdescribed more thoroughly in the “backing” section. These variousadhesives may be the same throughout the device, or more than oneadhesive may be comprised in the device, e.g., one adhesive may be usedto bind an array to the backing, and another adhesive may be used tobind the device to the skin or tissue of a patient. Furthermore,adhesive covers may be used, wherein the adhesive may again be the sameas the adhesive that is optionally comprised on the other variouscomponents of the device, or wherein the covers comprise a differentadhesive than the other various components of the device. Accordingly,the devices may comprise one or more types of adhesives.

In some instances, the device is a single base comprising a plurality,of microstructures fashioned into one or more arrays. In such anembodiment, the microstructures may be evenly spaced throughout anarray, or they may be unevenly spaced, e.g., one non-limiting embodimentcomprises a single base comprising at least two arrays, wherein thearrays are separated by an isthmus. Alternatively, the device maycomprise one or more bases; each base comprising a plurality ofmicrostructures fashioned into one or more arrays; wherein the bases areattached to a backing according to the present disclosure. In even otherinstances the microstructures are affixed to a backing or base, e.g.,via attachment of the individual microstructures.

Microstructure Arrays on the Devices

In some embodiments, the wound closure devices of the present inventioncomprise only one microstructure array. In one embodiment, the woundclosure devices comprise two microstructure arrays (e.g., separated byan isthmus). In certain embodiment, the wound closure devices comprise aplurality of microstructure arrays. In particular embodiments, the woundclosure devices comprise from two to 100 microstructure arrays.

Pluralities of arrays may be separated from one another by anyappropriate spacing, which may or may not be the same throughout thedevice. In some embodiments, array spacing ranges from approximately 30μm to 1 cm. Accordingly, array spacing may be approximately 30 μm, 50μm, 100 μm, 150 μm, 200 μm, 250 μm, 300 μm, 350 μm, 400 μm, 450 μm, 500μm, 550 μm, 600 μm, 650 μm, 700 μm, 750 μm, 800 μm, 850 μm, 900 μm, 950μm, 1 mm, 1.5 mm, 2 mm, 3 mm, 5 mm, 7 mm, 10 mm, or higher, includingall integer (e.g., 31 μm, 32 μm, 33 μm, etc.) and ranges (e.g., 100-1000μm, 500 μm-10 mm 700 μm-1 mm, etc.) in between, of the microstructureheights set forth herein. In one embodiment, the array spacing is from 2to 10 mm. In another embodiment, the array spacing is from 4 to 10 mm.

The arrays may be evenly, or unevenly spaced apart, e.g., directionallyvaried. In particular embodiments, at least two arrays are comprised onthe device, said arrays optionally being separated by an isthmus; whitein other embodiments no such isthmus separates the arrays. In furtherembodiments, the device may comprise a plurality of arrays on one oreither side of an isthmus, said plurality of arrays being optionallyevenly spaced apart from one another on each side of the isthmus, or notevenly spaced. In some embodiments, an equal number of arrays are oneither side of the isthmus, and in other embodiments an unequal numberof arrays are on either side of the isthmus.

In some embodiments, the wound closure devices of the present inventioncomprise two or more arrays comprised on a base, and/or optionallyaffixed to a backing, wherein the arrays are separated by an isthmus. Incertain embodiments the isthmus is not stretchable, while in otherembodiments it is stretchable. As a non-limiting example, one suchdevice comprises two arrays affixed to a backing, said arrays beingseparated by a non-stretchable isthmus; wherein the space comprising thearrays is not stretchable (e.g. FIG. 13a to 13e ). Another non-limitingexample of such a device in shown in FIG. 15a to 15e , wherein thedevice comprises two arrays affixed to a backing, and separated by anisthmus that is not stretchable. Furthermore, examples of suchembodiments are shown in FIGS. 18a to 20, as applied to human andsynthetic skin.

In some embodiments, the device comprises two or more arrays that arenot separated by an isthmus. Accordingly, two or more arrays mayoptionally be immediately adjacent to one another, thus having no spaceor substantially no space separating the arrays. A non-limiting exampleof such a device may comprise two separate microstructure arrays, eacharray having its own base, and each array being separated from oneanother by a distance that is equal to, or less than, the pitch of theirmicrostructures. Accordingly, such wound closure devices may be used toclose or secure a wound, wherein the microstructures comprised on thetwo or more arrays are located all the way up to the wound's edge.

Similarly, the present invention provides for devices comprising onlyone microstructure array, wherein a wound is closed or secured viaapplication of the device directly over the wound, such that some of themicrostructures comprised in the single array are secured on one side ofthe wound, and some of the microstructures comprised on the same arrayare secured on the other side of the wound. Furthermore, the wound maybe closed with a device comprising only one microstructure array, saidarray being longer and wider than the wound such that the microstructurearray completely covers the wound, so that microstructures are presenton substantially all sides of the wound, and are also optionally alsopenetrating into the wound.

In particular embodiments, the wound closure devices of the presentinvention comprise a plurality of microstructure arrays comprised on abase, and/or optionally affixed to a backing, such that at least onemicrostructure array is capable of penetrating into or grasping skin ortissue on one side of a wound, and at least one other microstructurearray, which is optionally separated from the first array by an isthmus,is capable of penetrating into or grasping skin or tissue on anotherside of the wound. In some embodiments, the device comprises a flexibleand stretchable backing. Such a device may be stretched across a woundsite by using traction and the grip of the microstructures onto the skinof a subject. Embodiments such as this may optionally comprise a backingor isthmus that comprises elasticity, such that the retractile force ofthe device helps to secure the device in place, and/or assists in theclosing the wound. In this way, in certain embodiments, the woundclosure devices of the present invention are able to pull together theskin directly adjacent to a wound, such that the wound is closed orsubstantially closed, or optionally everted. In other embodiments, thedevice is not substantially stretchable, and thus it is applied to awound that is closed by other means (e.g., suturing or with forceps) soas to secure the wound in its already closed position.

The arrays may be any appropriate shape, and in particular embodimentsthey comprise rounded edges, so as to reduce the induction of irritationand to limit accidental removal, as described above with regard to theshapes of the backings.

Device Areas and Densities

The wound closure devices can be any area suitable for a particularapplication. Large device areas are used for large wounds and smalldevices are used for small wounds.

In one embodiment, the device is less than 0.5 cm² in area, in oneembodiment, the device is less than 1 cm² in area. In one embodiment,the device is less than 1.5 cm² in area. In one embodiment, the deviceis less than 2 cm² in area. In one embodiment, the device is less than 3cm² in area.

The devices contain a density of microstructures per unit area. Incertain embodiments, the microstructure density is uniform throughout anarray or device. In another embodiment, the microstructure density isnot uniform.

In one embodiment, the device is less than 0.5 cm² area and contains2-20 microstructures. In one embodiment, the device is less than 1 cm²in area and contains 6-50 microstructures. In one embodiment, the deviceis less than 1.5 cm² in area and contains 10-100 microstructures. In oneembodiment, the device is less than 2 cm² in area and contains 20-200microstructures. In one embodiment, the device is less than 3 cm in areaand contains 50-300 microstructures.

Head and Neck Devices

Given that the largest fraction of skin biopsies and lacerations occuron the head, neck, and face, and the superior wound closure capabilitiesof the disclosed devices, in certain embodiments the devices areconfigured for relatively small-scale wound closure. In certain such“head and neck” devices, relatively short microstructures (e.g.,microneedles) are used to minimize inflammation and be able to penetratethe thin skin of the head, face, and neck compared to other skin sitessuch as the back and extremities. Examples of head and neck devices havelengths and widths of between 0.5 and 2 cm. Such a compact form comesfrom relatively small arrays and a short, or no, isthmus.

In one embodiment, the microstructure spacing is from 1-3 mm.

In one exemplary embodiment, the head and neck device has the followingcharacteristics: 1 cm×0.6 cm device: two arrays each being 3-4 mm inlength and 0.6 cm in width with 2-6 microstructures (e.g. microneedles)on each array, and an isthmus of 2-3 mm in length.

In one exemplary embodiment, the head and neck device has the followingcharacteristics: 1 cm×1 cm device: two arrays each being 3-4 mm inlength and 1 cm in width with 6-40 microstructures (e.g., microneedles)on each array and an isthmus of 2-3 mm in length.

In one exemplary embodiment, the head and neck device has the followingcharacteristics: 1.5 cm×1 cm device: two arrays each about 5-6 mm inlength and 1 cm in width with 10-60 microstructures (e.g., microneedles)on each array and an isthmus of about 5 mm in length.

In one exemplary embodiment, the head and neck device has the followingcharacteristics: 2 cm×1 cm device: two arrays each about 6-8 mm inlength and 1 cm in width with 15-100 microstructures (e.g.,microneedles) on each array and an isthmus is 6-8 mm in length.

It will be appreciated that additional head and neck devices arecontemplated that include any device size, microstructure type, arraytype, and related characteristics.

Roll Bandage

In some embodiments, the wound closure device of the present inventionis in the form of a roll. Roll wound closure devices according to thepresent invention are in some embodiments akin to a roll bandage, withthe important addition of the wound closing microstructure arrays. Suchmicrostructure array roll bandages comprise a slender, elongated shapeand are formed into a roll. They comprise various lengths and widths, alongitudinal axis, and a wound-facing isthmus extending along thelongitudinal axis (typically in the midline of the longitudinal axis),that is over the wound when the microstructure array roll bandage isbeing applied.

In certain embodiments, the microstructure array roll bandages eachcomprise three parallel longitudinal portions that are slender andelongated and include a middle portion (the wound facing isthmus) thatextends along the longitudinal axis of a backing upon which themicrostructure arrays are affixed. Such bandages further comprise twoexterior portions that extend along the longitudinal axis of thebacking, each of said two exterior portions comprising one or moremicrostructure arrays extending along the length of the bandage. In someembodiments, the bandage comprises one long array of microstructuresextending along the longitudinal axis, and in other embodiments aplurality of microstructure arrays are comprised upon this axis.

In another similar embodiment, the microstructure array roll bandages donot comprise a backing, but instead are comprised of microstructures ona base. Such a bandage may comprise three parallel longitudinal portionsthat are slender and elongated and include a middle portion (the woundfacing isthmus) that extends along the longitudinal axis of a base uponwhich the microstructure arrays are affixed. Such bandages furthercomprise two exterior portions that extend along the longitudinal axisof the base, each of said two exterior portions comprising one or moremicrostructure arrays extending along the length of the base. In someembodiments, the bandage comprises one long array of microstructuresextending along the longitudinal axis, and in other embodiments aplurality of microstructure arrays are comprised upon this axis.

As is the case with all of the devices of the present invention, rollbandages may optionally comprise other drugs or therapeutics, e.g., uponor along the isthmus: and likewise they may also optionally compriseadhesive, e.g. directly comprised on the backing or base, or optionallycomprised on tabs or strips protruding along the external portion of thebacking or base, said tabs or strips optionally being removable, e.g.,easily tearable due to perforations.

Targeted at, for instance, over-the-counter (OTC) users of bandages suchas, e.g., BAND-AIDs®, further embodiments may include a glueless woundclosure device, which is based on the present microstructure technology.Such embodiments may be used as alternatives to traditionally availablebandages attached to the skin with adhesive. Such embodiments may takethe form and shape of typical adhesive attached bandages. These productscan serve the needs of patients, who suffer minor cuts and burns inwhich bandages are used today. Further embodiments provide for devicessuch as these, comprising other components to aid in the attachment ofthe devices. e.g., nanostructures such as nanofibers. One suchnon-limiting example comprises the addition of a chitin nanofiber coatto the backing or to the microstructures. Due to their small size, thesenanostructures add surface area to the device, increasing the overallcontact with the wound or the surrounding tissue or skin. Accordingly,the added surface area induces a glueless adhesion, assisting in theproper placement and adherence of the device.

The devices of the present invention may further comprise a variety ofornamental designs, in some embodiments, the devices are substantiallytransparent, while in other embodiments they are not. Particularembodiments provide for devices as disclosed herein that comprise acolor or pattern, e.g., an animal print or themed design.

Optional Components

In particular embodiments, in addition to the microstructure arraysdescribed above, the wound closure devices of the present invention mayfurther comprise nanostructure arrays and/or nanofiber coatings upon themicrostructures. In such embodiments, the nanofiber coatedmicrostructure surfaces, or the nanostructure arrays, can increase thesurface area of the devices, thus in turn leading to increased contactof the device with the skin or tissue to which it is applied. As aresult, the devices may stick more efficiently, further promotingglueless adhesion, thus obviating the need for adhesive components.Accordingly, in some particular embodiments, the microstructures of thepresent invention are comprised of, or coated with, chitin nanofiberink, as disclosed in the co-owned PCT application (PCT/US2012/040565,herein incorporated by reference in its entirety).

In some embodiments the wound closure devices of the present inventioncomprise a visual stress indicator on the base or flexible backing. Incertain embodiments, the stress indicator is a painted strip or severalpainted strips that change color upon extension of the device.

In still further embodiments, the devices disclosed herein may includeone or more additional components that are provided to, for example,reduce pain, improve healing, reduce adhesion to the wound, preventinfection, reduce itching, or otherwise aid in improving patientcomfort. Such additional components are described below and can beincorporated into the wound closure devices of the present invention inany suitable location (e.g., on an isthmus or on one or more arrays), orthey can alternatively be provided and/or used to treat a wound prior tothe application of the present wound closure devices.

In some embodiments the wound closure devices of the present inventionfurther comprise a hydrogel. The hydrogel may be comprised of anysubstance. Some embodiments provide for hydrogels comprising, consistingessentially of, or consisting of an inert substance, or mixtures ofinert substances, in some embodiments, the hydrogel comprises abiopolymer. In certain embodiments, the hydrogel comprises abiologically active substance, and some particular embodiments, thehydrogel comprises a biologically active substance that is able toinduce or promote wound healing. In one embodiment, the hydrogelcomprises chitin, chitosan, or a mixture of chitin and chitosan. Incertain embodiments, the wound closure devices of the present inventioncomprise hydrogels as described herein, wherein the hydrogel isconnected to the flexible backing. Hydrogels may be connected to thebacking in any suitable location. In some particular embodiments, thehydrogel is connected to an isthmus. In some particular embodiments, thehydrogel is connected to a flexible backing in a space within amicrostructure array, e.g., between at least two microstructures. Insome particular embodiments the hydrogel is directly connected to one ormore microstructures, e.g., as a coating.

In some embodiments, other healing agents are optionally comprised on,or used with the wound closure devices, such as, e.g., chitosan, chitin,alginates, silver, silicone, iodine, antimicrobials, cytokines, growthfactors, honey, leptospermum honey-, polyhexamethylene biguanide,methylene blue, gentian violet, and combinations thereof. Accordingly,in such embodiments, these other agents may be optionally applied to thewound or the device by the user, prior to the application of the device.Alternatively, in some embodiments these other agents may be comprisedon the device as packaged (e.g., on an isthmus or on an array). Theagents may be applied in the form of a powder, cream, gel, ointment, orother formulation know to those of skill in the art.

Covers

Some embodiments of the present invention provide for the optionalapplication of one or more protective covers over the top of the woundor wound closure device; e.g., to provide additional protection to thewound from the surrounding environment, and to help maintain the devicesecurely in its intended position. Indeed, we have found that in someembodiments the devices are much more strongly secured in their intendedposition when covered in this manner. In principle, any cover willsuffice. In some embodiments, optimal covers will be such that they areable to apply additional downward force upon the device to ensure themicrostructures remain in place and to prevent unintentional removal ofany of the microstructures. The covers may be any appropriate shape, andin particular embodiments they comprise rounded edges, so as to reducethe induction of irritation and to limit accidental removal, asdescribed above with regard to the shapes of the backings.

In some embodiments, the cover comprises adhesive, while in otherembodiments it does not. The adhesive may optionally be such that itsticks permanently to the device, but temporarily to the skin or tissue,such that any attempt to remove the cover will result in a simultaneousremoval of the device. In such an instance, the device and/or cover mayoptionally be replaced with a new device and/or cover if necessary. Insome embodiments, the cover may be designed such that it does notpermanently adhere to the device, but it can instead be removed andoptionally replaced with another cover without disturbing the placementof the device on the wound. Alternatively, one can remove such atemporary cover so as to replace one or more of the devices. Of course,anew cover can then optionally be applied such as needed. In otherembodiments, only a portion of the cover contains adhesive, such asdescribed herein.

In some embodiments the cover may be optionally flexible and/orstretchable. In some embodiments, the cover is transparent, orsubstantially transparent, thus allowing for non-invasive monitoring ofwound healing: while in other embodiments the cover is not transparent.In some embodiments, the covers are in the form of sheets; bandages;films or other permeable, semi-permeable, or impermeable coverings. Thecovers may be made from natural, synthetic, and/or artificial materials;and in some particular embodiments, they comprise a polymeric substance(e.g., a silicone, a polyurethane, or a polyethylene). In someembodiments, the cover is comprised of materials that are nontoxic,biodegradable, bioresorbable, or biocompatible. In some embodiments, thecover comprises inert materials, and in other embodiments, the covercomprises activated materials, in some embodiments, the cover furthercomprises elastic properties, wherein the elasticity may optionally besimilar throughout the cover, or it may be varied along or across thecover. Furthermore, in some embodiments, the covers comprise adhesive,while in other embodiments they do not. Accordingly, in someembodiments, the cover comprises a material singularly, or incombination, selected from the group consisting of tape (e.g., medicaltape, white cloth tape, surgical tape, tan cloth medical tape, silksurgical tape, clear tape, hypoallergenic tape), silicone, elasticsilicone, polyurethane, elastic polyurethane, polyethylene, elasticpolyethylene, gauze, gel, hydrogel, silk, chitin, chitosan, cellulose,alginate, foam, shrink wrap, sheets, and hydrocolloids.

In particular embodiments, the cover is a commercially available coverselected from the group consisting of Brown Medical—Sealtight ShowerDressing Protection Patch; Smith & Nephew Coversite Composite CoverDressing; Coloplast Comfeel Plus Hydrocolloid Clear Thin Dressing;Systagenix Nu-Derm Bordered Hydrocolloid Wound Dressing; 3M TegadermHydrocolloid Dressing; Smith & Nephew Replicare Thin HydrocolloidDressing; Smith & Nephew Replicate Hydrocolloid Wound Dressing;Hollister Restore Sterile Hydrocolloid Dressing; Hollister RestoreHydrocolloid Dressing with Foam; Backing; Hollister Restore PlusHydrocolloid Dressing with Tapered Edge; Kendall Polyskin II TransparentDressing; Smith & Nephew AlgiSite M Calcium Alginate Dressing; KendallCurasorb Calcium Alginate Dressing; Deroyal Kalginate Calcium AlginateDressing; Smith & Nephew Cica-Care Silicone Gel Sheeting; MolnlyckeMepiform Safetac Self Adherent Dressing with Soft Silicone for ScarReduction; Molnlycke Mepitel Safetac Transparent Wound Contact LayerSmith & Nephew OpSite Flexifix Transparent Film Roll; Systagenix SelectBioclusive Transparent Wound Dressing; Systagenix Select BioclusiveTransparent Wound Dressing; 3M Tegaderm Transparent Dressing First AidStyle; 3M Tegaderm Clear Absorbent Acrylic Dressing; Hartmann CosmoporeAdhesive. Wound Dressing; 3M Tegaderm Transparent Film Dressing withBorder; Kendall Telfa Sterile Clear Wound Dressing; Smith & NephewAllevyn Thin Gentle-Adhesive Polyurethane Dressing; and combinationsthereof.

In some embodiments the cover is comprised in a roll, optionallycomprising adhesive. In some embodiments the roll bandages may becovered by an adhesive cover, e.g., an adhesive roll cover. In otherembodiments, the roll bandages are covered by a plurality of adhesivecovers, e.g., a plurality of sheet covers.

In some embodiments, the wound closure devices are disposable.Accordingly, disposable devices may contain components that make it notpossible to apply more than once. For example, but not to be limited inany way, disposable devices may comprise a backing or wound cover thatcontains adhesive material that is not adherent once removed from theskin. In another non-limiting example, an adhesive cover may be used,wherein following application, the cover is designed to adhere to thewound closure device in such a way that they cannot be separated fromone another without destroying the device. In another non-limitingexample, the microstructures may be made of biodegradable material. Suchdisposable designs may prevents the risk the device being used on morethan one patient, which can result in transmission of infectious agents;and will also reduce the risk of reapplication on the same patient,which may increase the risk of infection.

Packaging

The wound closure devices of the present invention may be packagedindividually, e.g., in a single use stand alone package, oralternatively, a plurality of the devices may be packaged together inany way, e.g., in a receptacle containing a plurality of individuallypackaged single use wound closure devices, or e.g., in a roll comprisinga plurality of devices (optionally individually packaged) and separatedby a cuttable or tearable connecting portion. Accordingly, someembodiments provide for a roll comprising a plurality of individuallypackaged wound closure devices, as described herein, wherein each of theindividually packaged devices are connected to at least one otherindividually packaged device via a perforated connecting portion, thusenabling the easy separation of one of said individually packagedbandages.

In some embodiments, a plurality of the wound closure devices of thepresent invention may be packaged together in the form of a roll; oralternatively the wound closure device may be a microstructure arraybandage, as described herein. Accordingly, the present disclosure alsoprovides for a roll-on, handheld dispenser to assist in the easyapplication of the present wound closure devices. Although applicable inthe at-home setting, this embodiment is specifically designed with thesurgical market in mind (e.g. specifically urgent care settings, such asemergency rooms and operating rooms where time is of the utmostimportance) With rapid single hand operation, such an embodiment offerssignificant advantages over sutures, which require precious time to use,or Steri-Strips, which are difficult to handle and are only able toclose minor wounds.

The design of such embodiments may be compared to white tape dispensersused to correct errors on paper. This embodiment may contain a roll keptin a sealed enclosure to ensure its sterility. Tapes or bandages canhave various widths tailored to the needs of various medical and otheruses. For instance, such tapes or bandages may have widths of 0.5 cm, 1cm, or more. By applying the device with the dispenser to the woundedarea, the provider of medical care will be able to rapidly use thisembodiment with its strong mechanical and adhesive properties to securewound closure without painful sutures. The microstructure technologywill ensure that, upon contact with the patient skin, themicrostructures will adhere and allow for dispending further material.The microstructures will be designed to minimize adhesion to the back(the surface that is away from the skin) of the microstructure mil toensure rapid and convenient delivery. A microstructure dispenseraccording to the present invention may include a means for cuttingspecifically designed to cut the microstructure tape or roll withoutdamaging the patient skin. In some embodiments, the blade can be placedat an angle that allows for microstructure tape cutting upon an upwardrotation of the medical care provider's hand. This single hand operationwill afford speed and accuracy of the closure of wounds. The medicalcare provider will be able to use the other hand to ensure skinplanarization during wound closure. Not only is this more convenient forthe medical care provider, but it also eliminates the need for othermedical personnel to assist the surgeon in carrying out wound closure.

Wound Closure System Kit

In some embodiments the devices of the present invention are provided asa wound closure system, which is a kit comprising at least one woundclosure device, as described herein, and at least one other componentthat can optionally be used with the device. e.g., to improve woundhealing capabilities. Kits such as these may comprise one or more of thewound closure devices disclosed herein, as well as one or more otheroptional components such as, e.g., one or more covers (optionallycomprising adhesive) to be applied over the wound closure device; one ormore container (e.g., bottles, pouches, packets, tubes) comprising adrug or therapeutic, cleansing and/or sterilization means (e.g.,antiseptics, antibiotics, sterile saline), analgesics (e.g., Benzocaineor Lidocaine), which can optionally be applied to the wound prior to theapplication of the device; and instructions for using the wound closuredevices.

In such embodiment, a wound closure system comprising one or more of thepresently disclosed wound closure devices, and optionally comprising oneor more of the aforementioned optional components, further compriseschitin and/or chitosan. Chitin and chitosan alike: 1) promote healing,2) are anti-bacterial, 3) prevent bleeding (homeostasis), 4) decreaseinflammation, 5) reduce scarring, 6) absorb fluids such as exudate, and7) are breathable; thus their addition to a wound prior to closure cansignificantly improve the healing process. The chitin or chitosan may bein any suitable form, and in some embodiments they are in the form of apowder, a gel, a cream, or an ointment. The chitin or chitosan may beapplied to the wound or device prior to the application of a woundclosure device, such that the natural healing properties of theseproducts may promote healing. Alternatively, the device may comepackaged with the chitin or chitosan already on the device at anysuitable location, e.g., on or around the microstructures or on anisthmus.

In one particular embodiment, the kit may comprise one or moremicrostructure arrays (separate from a backing); one or more backings(e.g.; optionally different kinds of backings upon which the arrays canbe affixed), thus enabling the usr flexibility to tailor the exactdesign of the device to the specifications of a particular wound); ameans for attaching one or more of the arrays to one or more of thebackings (e.g., a glue); a cover; and chitin or chitosan (e.g., in theform of an ointment, gel, cream, or powder).

In another particular embodiment, the kit may comprise one or moremicrostructure arrays affixed to a backing; a cover; and chitin orchitosan (e.g., in the form of an ointment, gel, cream, or powder).

In another embodiment, the kit comprises a cutting instrument (e.g.,disposable scissors) configured to cut the devices, arrays, and/orbackings, such that is possible for a user to individually fabricate anarray to the desired dimensions. This enables the user to tailor thewound closure device to the specific dimensions and other characteristicof an individual wound.

Additionally, all kits optionally further comprise instructions for useof the present devices.

Use of the Devices

The wound closure devices of various embodiments can be used to treatany kind of wound including acute and chronic wounds, such as, e.g.,lacerations, cuts, scrapes, abrasions, post-operative wounds (e.g.,caused by minimally invasive surgery, laparoscopic surgery, roboticsurgery, incisional biopsies, general surgery, and cosmetic surgery)denuded skin, burns, ulcers (e.g., diabetic ulcers, ulcers from vascularinsufficiency, pressure sores), or other skin problems (e.g., allergies,eczema, dermatitis, and psoriasis). Accordingly, wound closure devicesof various sizes can be prepared such that minor wounds as well aslarger wounds can be treated using the devices of embodiments. Inparticular embodiments, the wounds treated with the devices of thepresent invention range from approximately 0.1 mm in length, toapproximately 50 cm in length. Accordingly, in particular embodiments,the wound length is approximately 0.1 mm, 0.2 mm, 0.3 mm, 0.4 mm, 0.5mm, 0.6 mm, 0.7 mm, 0.8 mm, 0.9 mm, 1 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm,1 cm, 2 cm, 3 cm, 4 cm, 5 cm, 10 cm, 20 cm, 30 cm, 40 cm, 50 cm, orlonger, including all integers and decimals (e.g., 9.1 mm, 9.2 mm, 9.3mm, etc.) and ranges (e.g., 0.1 mm-50 cm, 0.5 mm-10 cm, 0.5 mm-5 cm,etc.) in between, of the wound lengths set forth.

The wound closure devices can be used to close an entire wound or aportion of a wound. Multiple wound closure devices of the same ordifferent design may be used together to close a given wound. When aplurality of the wound closure devices are used to close a single wound,they may be placed immediately adjacent to one another (either runningparallel or perpendicular to the wound), or they may be separated fromeach other at any suitable distance. Accordingly, the devices may beapplied with no space between the arrays of two different devices, orthey may be applied approximately 2 cm apart, or more. In particularembodiments, pluralities of wound closure devices are affixed to a woundaccording to the present disclosure with a spacing that ranges fromabout 2 mm to about 10 mm.

The wound closure devices can also be used in combination with otherwound closure devices, such as sutures, staples, tissue adhesives, andbandages. The wound closure devices can also be used for temporary woundclosure prior to closure with other devices, such as staples, sutures,or tissue adhesives. The wound closure devices can also used afterclosure with sutures or staples. For example, this could enable earlierremoval of sutures and staples, and thus reduce the risk of scarringrelated to these devices.

The wound closure devices can be used alone or with wound dressings,including transparent films, gauzes, hydrofibers, hydrogels,hydrocolloids, exudative absorbers, collagens, and alginates. Thedevices can also be used with impregnated dressings containing bismuth,petroleum, silver, and carboxymethylcellulose.

The wound closure devices disclosed herein may be applied in anysuitable manner. For example, but not to be limited in any way, in someembodiments, wherein a wound comprises a length to width aspect ratioother than 1 (e.g., a laceration), the wound closure device may in oneembodiment be applied perpendicularly, with respect to the longerportion of such a wound, thus bridging the slit of the wound, oralternatively, the devices may be applied parallel to the slit of thewound, e.g., wherein a microstructure array wound bandage roll is rolledover the wound. In still further embodiments, the devices of the presentinvention may be applied to such a wound at a diagonal, with respect tothe slit of the wound. Additionally, as needed, some embodiments providefor the utilization of a plurality of the wound closure devices to treata particular wound. In such embodiments, the devices may be applied to awound in any appropriate manner, so as to achieve the desired woundclosure effect. Non-limiting examples include, e.g., the application oftwo or more of the wound closure devices in parallel to one another,perpendicular to one another, or even criss-crossed over one another. Insome embodiments the device is stretched across a wound, and in otherembodiments the device is applied without stretching. In someembodiments the device is applied by hand, and in some embodiments thedevice is applied using an applicator or instrument, as described morethoroughly below. In some embodiments, multiple wound closure devicesmay be used to close an individual wound. Any number of devices may beused to close a given wound, in any orientation, and said devices may bespaced apart from one another at any appropriate distance, so as toachieve the desired wound closing effect.

In general, the wound closure devices of the present invention arecapable of closing or protecting a wound, while optionally also enablingefficient and versatile delivery of drugs or therapeutic agents. FIG. 16shows a schematic representation of a cross sectional view of a woundclosure device applied to a wound. In this embodiment, relatively longmicrostructures are shown penetrating the epidermis and into the dermisof the adjacent skin on either side of the wound. In this way the woundis secured closed. Depending on the desired application, microstructureslength can be varied e.g., using shorter microstructures to inducetopical drug delivery to the epidermis, systemic delivery viamicrostructures long enough to penetrate the dermis, or variousintermediate lengths to target drug or therapeutic delivery toparticular dermal and epidermal sublayers. One skilled in the art iseasily able to determine the necessary length of the microstructures totarget a specific layer, a property that will vary depending on thelocation to which the device is intended to be used. For example, iftargeting the dermal layer of the eyelid, one must account formicrostructure lengths in the range of 0.3 mm. If however, one needs totarget the dermal layer of the back, microstructures lengths must be anorder of magnitude longer, e.g., 3 mm.

Accordingly, in some embodiments, the wound closure devices of thepresent invention provide their desired function in the absence of otherknown drugs or therapeutic agents, and in other embodiments, the devicesprovide their desired function in combination with other drugs ortherapeutic agents. In some particular embodiments, the presentinvention provides for wound closure devices comprising e.g., hollowmicrostructures in which drugs or therapeutics can be incorporated e.g.,as are described in U.S. Pat. No. 3,964,482, incorporated by referenceherein in its entirety; porous microstructures; drug or therapeuticcoated microstructures; and microstructures comprising slow releasemechanisms for controlled drug or therapeutic delivery.

The wound closure devices described herein can be used to treat woundson humans or any other animal including, but not limited to, mammals,fish, reptiles, birds, and other creatures. Thus, medical and veterinaryuses for the wound closure devices described herein are encompassed bythe invention, and such uses can be carried out by trained medicalprofessionals, physicians, veterinarians, nurses, emergency medicaltechnicians, and the like, or by consumers who purchase the devicedescribed herein over the counter.

EXAMPLES Example 1 Microstructure Fabrication

The following example outlines one of many suitable methods forproducing microstructures and microstructure arrays according to thepresent specification. In this particular example, microstructures wereproduced using a replica molding technique that is commonly used withinthe art, and can be easily reproduced by the skilled artisan.

FIGS. 1a to 1f show a schematic demonstrating the main steps in thisprocedure. To begin, a master mold of the desired dimensions was madeout of aluminum via micromachining and wet chemical etching. Apolydimethylsiloxane (PDMS) mold (Sylgard 184 Silicone Elastomer Kit,Dow Corning Corporation, 3097358-1004) was prepared from, the master bypouring the recently mixed components of the PDMS on top of the masterinside of an aluminum foil box desiccating for 15 minutes, and thenallowing the components to cure on a hot plate at 110 C for 1 hour. PMMA(Sigma Aldrich 445746-500G) was dissolved in acetone to form a 10 wt. %solution and then poured over the mod with a 3 mm solution height. Afterdrying for approximately 3 days, all of the acetone had vaporized andthe microstructures were peeled from the mold and then stored in a cellculture dish until needed. Finally, microstructures were affixed to aSteri-Strip S piece by gluing with Loctite 4011 medical adhesive. FIGS.2a to 2 c are photographs of several different microstructures that wereproduced via this technique, with A and C being straight microneedlesand B being angled microblades. FIGS. 7a, 7b, 12a, and 12b are images ofnonlimiting examples straight microneedle arrays and angled microbladearrays, respectively, each patterned in low density (FIGS. 7a and 12a )and in high density (FIGS. 7b and 12b ); thus demonstrating some of themicrostructure variety that can be produced via this method. FIGS. 14ato 14e and 17a to 17c show non-limiting prototype examples of woundclosure devices comprising microstructure arrays produced via thismethod.

Example 2 Wound Closure Devices

The following example demonstrates a non-limiting selection of severalwound closure devices we have made. In principle, microstructures can beeasily fashioned into any conceivable shape using microfabricationtechniques common to the art, e.g., via the replica molding methoddescribed in Example 1. Furthermore, although PMMA was used for all ofthe devices shown in this Example, a variety of microstructures andmicrostructure arrays were formed out of other material, (e.g., chitin),and one skilled in the art can easily fashion similar microstructuresfrom a myriad of other materials such as, e.g., the various materialdescribed in this specification, and hundreds of other materials knownto the skilled artisan to be suitable for such microfabrication.Accordingly, it is without limitation that we present these particularembodiments, as an example of the specific versatility of thistechnique.

Prototype A.

These devices all comprised two microstructure arrays which weremanufactured according to the method described in Example 1; wherein twobases, each comprising a single microstructure array were affixed to apolyurethane backing derived from Steri-Strip S material. The backingscomprising the arrays were separated by a polyester filament isthmus.FIG. 17a shows a picture of one of these prototypes. In this picture,the backing materials are 1.5 cm wide×3 cm long. Arrays are 8 mm wide×12mm long, comprising straight microneedles made of PMMA, which are 550 μmlong, and uniformly distributed in the arrays. The isthmus is 15 mmlong, with a 22 mm separation between the two microstructure arrays,During production of this prototype, many other models were made,varying different components such as, e.g., the isthmus length/distancebetween needle arrays; the placement of the needle arrays within thebacking; the length of tabs on opposing sides behind the needle arrays;the presence or absence of adhesive on the tabs and/or on the isthmusareas; types of microstructures, size of microstructure arrays used, anddensity of microstructures.

Prototype B.

These devices all comprised two microstructure arrays which weremanufactured according to the method described in Example 1; wherein twobases, each comprising a single microstructure array were affixed tosingle polyester filament backing derived from a single Steri-Strip Smaterial. The bases are positioned with varying lengths of separation tocreate a variety of isthmus lengths. FIG. 17b shows a picture of one ofthese prototypes, in this picture, two microblade arrays were affixed ona polyester filament that is 22 mm in length with a 5 mm isthmusseparation. Each arrays is 11 mm wide×4.5 mm long, comprising 900 μmlong PMMA microblades in a configuration of 8 angled microblades×3angled microblades that were uniformly distributed throughout the array.The two arrays are separated by 5 mm. The tabs on either end of thedevice comprise an acrylate adhesive (present on the Steri-Strip S),During production of this prototype, many other models were made,varying different components such as, e.g., the isthmus length (i.e.,distance between microstructure arrays); the length of tabs on opposingsides behind the arrays; the presence or absence of adhesive on the tabsand/or on the isthmus areas; types of microstructures, size ofmicrostructure arrays used, and density of microstructures.

Prototype C.

These devices all comprised two microstructure arrays which weremanufactured according to the method described in Example 1; wherein twobases, each comprising a single microstructure array were affixed tosingle backing made of paper/fiber mixture with added polyester filamentsupports for strength (This backing has some flexibility to allow it toconform to the skin; while still allowing the wound to be closed) whichwas derived from Steri-Strip (Note: Not Steri-Strip S) material. Thebases are positioned with varying lengths of separation to create avariety of isthmus lengths. FIG. 17c shows a picture of one of theseprototypes. In this picture, two microneedle arrays were affixed on a 45mm polyester filament with a 8 mm isthmus separation. Each array is 10mm wide×6 mm long, comprising 1 mm long PMMA needles in a configurationof 7 straight needles×4 straight needles that were uniformly distributedthroughout the array. The tabs on either end of the device comprise anacrylate adhesive (contained on the Steri-Strips). The two microneedlearrays are separated by 8 mm. During production of this prototype, manyother models were made, varying different components such as, e.g., theisthmus length (i.e., distance between needle arrays); the length oftabs on opposing sides behind the needle arrays: the presence or absenceof adhesive on the tabs and/or on the isthmus areas types ofmicrostructures, size of microstructure arrays used, and density ofmicrostructures.

Summary

In this example, the versatility of the present wound closure deviceswas demonstrated. As shown, it is possible to vary the dimensions (e.g.,size, shape, width, and length) of the microstructures and arrays; type(see FIGS. 7a and 7b , and FIGS. 12a, and 12b , which show microneedleand microblade arrays, respectively) and angles of the microstructureswhich are provided upon bases of various lengths and widths. It is alsopossible to fashion microstructure arrays of variant size; shape; andmicrostructure density. It is also possible to fashion wound closuredevices comprising a variety of backings/isthmus sizes; materials; arrayconfigurations, etc. Accordingly, the present wound closure devices ofthe present invention provide a highly versatile wound closure systemwhich can provide a myriad of wound closure devices capable of beingfine tuned to the specific requirements necessary for closing a broadspectrum of different types of wounds in a variety of different tissuesand skin.

Example 3 Microstructure Array Traction Analysis

The following example outlines a preliminary analysis we performed todetermine if the microstructure arrays were capable of gripping andholding skin. The aim of this study was to:

-   -   To assess whether wound closure devices comprising angled        microblades could adhere to skin.        A 15 mm×28 mm segment of Steri-Strip S with 8 mm×12 mm array of        C2 microblades (8×4 microblades uniformly distributed. See FIG.        2b ) was attached to a 2.5×2.5 cm piece of fresh porcine skin        (2-3 mm thick). The porcine skin was previously glued onto a        Plexiglass slide, rinsed with 0.9 wt % saline solution, and        patted dry with gauze prior to testing. Traction was measured        with a tensile tester by mounting the needle on one side of the        tester (Shimadzu AGS-X) and the skin on the other and then        applying a pulling force.

Results

The results of this experiment are shown in FIG. 21. The Y axis of thegraph is force measured in Newton, and the X axis is displacementmeasured in millimeters. The angled needles were able to efficientlygrip the porcine skin, indicating such a device will be able to close awound, as intended.

Example 4 Preliminary Human Study

The following example outlines a preliminary human study that wasperformed to compare three different wound closure devices of thepresent invention. The aims of this study were as follows;

-   -   To assess whether application of the devices induces pain    -   To test adherence of the devices to human skin    -   To monitor inflammatory responses induced by the devices

The wound closure devices were placed on the volar surfaces of theforearms of 3 healthy human volunteers, and discomfort/pain,inflammatory responses and the stability of the device placement wereobserved on a daily basis for up to 8 days. The devices were affixed tothe skin (with no wound) by pressing down on one of the arrays and thenpulling in a lateral direction to stretch the skin and then affixing theother array to the skin so that the skin in between the two arrays iscompressed together to simulate the procedure that would be used toclose a wound.

Wound Closure Devices

The wound closure devices used in this study all comprised microneedlesand bases that were made out of PMMA. Base thickness was approximately140 μm. Each wound closure device contained two microstructure arrays,which were approximately 1 cm×1 cm in dimensions. Devices A and Bcomprised microneedles, while Device C comprised microblades. Thedevices each comprised a backing made out of Steri-Strip S® material,which was attached to the arrays with an 8 mm long isthmus separatingthe two arrays. Additionally, the Steri-Strip-S® material extended 6 mmbeyond the distal end of each array. The Steri Strip-S® materialnormally contains adhesive; however, the adhesive was covered up priorto application onto the skin of the volunteers so that the devices couldbe tested for adherence without adhesive. Also, after application to theskin, the devices and adjacent skin were covered with an adhesivepolyurethane tape cover (3M 9833) that was approximately 4 cm×4 cm. Thefollowing devices were tested.

Device A

-   -   Each microneedle in the array was in the shape of a pyramid and        was at a 90 degree angle to the base of the array    -   Each microneedle had the following dimensions: 1 mm length, 420        microns width at the foundation, and 60 micron tip diameter.    -   The microneedles were uniformly distributed at a pitch of 1.5        mm, and there were a total of approximately 50 microneedles in        each array.

Device B

-   -   Each microneedle in the array was in the shape of a pyramid and        was at a 90 degree angle to the base of the array.    -   Each microneedle had the following dimensions: 1 mm length, 420        microns width at the foundation, 60 micron tip diameter.    -   Arrays on opposing sides of the wound were positioned such that        the angled microneedles were angled towards the wound.    -   The microneedles were uniformly distributed at a pitch of 3 mm        and there were a total of 16 microneedles in each array.

Device C

-   -   Each microblade in the array was in the shape of a pyramid and        was at a 51 degree angle to the base of the array.    -   Each microblade had the following dimensions: 900 micron length,        1050 micron width at the foundation, approximately 130 micron        tip width, approximately 20-30 micron tip thickness.    -   Arrays on opposing sides of the wound were positioned such that        the angled microblades were angled towards the wound.    -   The microblades were uniformly distributed at a pitch of 4.5 mm,        and there were a total of 9 microblades in each array.

Device Application

The wound closure devices were placed on the skin using the followingprocedure: The adhesive strip attached to the distal end of one of thearrays was pressed down upon by hand, to enable attachment to the skin.Pressure was then applied over the closest array using the thumb. Whilethe thumb remained press down on the first array, the distal end of theother array was pinched between 2 fingers and gently stretched laterallyto simulate closure and eversion of the wound. After placement of thedevice, the device was covered with a medical adhesive cover (catalogno. 9833, 3M).

Results

Volunteers reported mild pain upon application of the devices(approximately 1-2 on a visual analog score (VAS) of pain ranging from 0to 10). Pain disappeared within an hour and then the devices werepainless for the duration of their application to the skin (2-8 days).

The wound closure devices remained on the skin for a range of 2 to 8days. Observations were made on a daily basis. All devices remained inplace and appeared to be firmly attached to the skin for the entireperiod of application. For Device A, erythema appeared in the skin incontact with the array approximately 3 days after placement of thedevice. When the array was removed swelling (edema) was also observed.The skin returned to normal appearance after approximately 2-4 weeks.For the other devices, there was no evidence of erythema, edema orinflammation at the skin sites where these devices remained in, placefor up to 8 days. Small puncture wounds were noted where the needlesentered the skin which disappeared after 24-49 hours at which point theskin returned to normal appearance for Devices B and C.

Summary

In summary, the results of the present study showed that the devices canbe applied with little induction of pain. All of the devices remainedfirmly attached to the skin for several days. Devices with more pitch (3mm or more) did not result in skin inflammation (erythema and edema),while the device with a pitch of 1.5 mm did show evidence ofinflammation. Therefore, without being limited by theory, it appearsfrom this preliminary study, that reducing the density and number of themicrostructures in the array may result in less inflammation, withoutcompromising the ability of the device to remain attached to the skin.These and other data (e.g., Example 5) strongly support that the presentwound closure, devices provide an attractive alternative to the priorart methods of wound closure.

Example 5 Porcine Wound Closure Study

The following example outlines a preliminary animal study that wasperformed to assess the wound closing efficiency of three differentwound closure devices of the present invention; and to compare theseefficiencies with wound closing efficiency of sutures. The aims of thisstudy were as follows:

-   -   To test adherence of the devices to wounded skin    -   To assess the devices ability to close a wound    -   To monitor inflammatory responses induced by the devices    -   To assess the ability of the devices to promote healing    -   To compare the results above between the devices and sutures        used to close wounds

Procedure of the Study

A neonatal porcine was used for the present study (note: neonatalporcine skin closely approximates the biomechanical properties of humanskin), and is a standard animal model for testing wound closure devices.Using a scalpel, full thickness wounds, each of 3 cm in length, weremade in, the skin on the dorsum of the thoracic area of the animal undergeneral anesthesia. Wounds were made on each side of the center of theposterior of the animal; and wounds on the same side were approximately5 cm from one another (FIGS. 22a and 22b ).

The wound area was shaved, and then cleaned with a standard antisepticsolution. Using aseptic technique, a 3 cm full thickness incision wasmade with the scalpel (FIG. 2c The wound was blotted dry with sterilegauze and then the wound was closed with the wound closure devices (FIG.23). Each wound was then closed with a different type of wound closuredevice, with two identical devices being applied to each wound.Additionally, as a control, one of the wounds was closed with sutures ina similar manner, wherein three sutures were applied to the wound (FIG.23).

Wound Closure Devices

The wound closure devices used in this study all comprisedmicrostructures and bases that were made out of PMMA according to themethod described in Example 1. Base thickness was approximately 140 μm,Each wound closure device contained two microstructure arrays, whichwere approximately 6 mm×10 mm in dimensions. The devices each compriseda backing made out of Steri-Strip® material, which was attached to thearrays with an 8 mm long isthmus separating the two arrays.Additionally, the Steri-Strip® material extended 6 mm beyond the distalend of each array. The following devices were tested.

Device A: Straight Microneedles (i.e., 90° Angle)

-   -   Each microneedle in the array was in the shape of a pyramid and        was at a 90 degree angle to the base of the array.    -   Each microneedle had the following dimensions: 1 mm length, 420        microns width at the foundation, and an approximate 60 micron        tip diameter    -   The microneedle were uniformly distributed at a pitch of 3 mm,        and there were a total of 12 microneedles in each array.    -   FIG. 7a shows a photograph of one of these arrays.

Device B: Angled Microblades (i.e., 51° Angle)

-   -   Each microblade in the array was in the shape of a pyramid and        was at a 31 degree angle to the base of the array.    -   Each microblade had the following dimensions: 900 micron length,        900 micron width where the microblade meets the foundation,        approximately a 130 micron tip width, and approximately 20-30        micron tip thickness,    -   The microblades were uniformly distributed at a pitch of 4.5 mm,        and there were a total of 6 microblades in each array.    -   Arrays on opposing sides of the wound were positioned such that        the angled microblades were angled towards the wound.    -   FIG. 12a shows a photograph of one of these arrays.

Device Application

On Day 0, the wound closure devices were placed on the skin of theporcine using the following procedure: the adhesive strip attached tothe distal end of one of the arrays was pressed down upon using thefingers of one hand, to enable attachment to the skin. Pressure was thenapplied over the closest array using the thumb. While the thumb remainedpress down on the first array, the distal end of the other array waspinched between two fingers and gently stretched laterally to enableclosure of the wound and enable eversion of the wound. This same processwas repeated in placing the second wound closure device. After placementof the two wound closure devices, the wound area was covered withTegaderm®.

Results

The wounds were observed daily for 12 days, with scoring forinflammation, infection, dehiscence, erythema, and edema. Furthermore,photos were taken to document the healing process. On Day 9, thedevices/sutures were removed, Pictures showing the wounds on Day 1 (oneday after placement of devices/sutures), Day 6, and Day 9 (10 days afterplacement of devices/sutures) are presented in FIGS. 23-26, and a briefsummary of the results is presented below,

Inflammation

On Day 1, inflammation was observed around the wounds that were closedwith device B and with sutures, however no such inflammation was inducedby wound closure device A. On Day 6, the sutured wound was stillinflamed, but no such inflammation was observed around the wounds closedwith devices A and B. On Day 9, inflammation was still observed aroundthe wound closed with sutures, however no inflammation was observedaround the wounds closed with device A or B.

Infection

No infections were observed on any of the wounds on Day 1, Day 6 or Day9, regardless of the wound closure method.

Dehiscence

No dehiscence was observed on any of the wounds on Day 1, Day 6, or Day9, regardless of the wound closure method.

Erythema

Erythema was observed around the sutured wound on Day 1, Day 6, and Day9, with the Day 9 erythema having a Draize Score of 2, according to theDraize scale of 0-4. On Day 1, but not Days 6 or 9, erythema was alsoobserved around the wound that was closed with device B. Device A didnot induce erythema.

Edema

No edema was observed on any of the wounds on Day 1, Day 6, or Day 9,regardless of the wound closure method.

Summary

In summary, the results of the present study showed that devices A and Bcan both effectively close a wound, with comparable efficiency to thatof sutures. Additionally, the wound closure devices disclosed hereinprovided the added benefit of not inducing lasting inflammation orerythema, wherein both of these adverse reactions were induced andremained for the 10 day observation period in the wound closed bysuturing. Thus the devices of the present invention provide anattractive alternative to sutures, for wound closure.

The various embodiments described above can be combined to providefurther embodiments. All of the U.S. patents, U.S. patent applicationpublications, U.S. patent application, foreign patents, foreign patentapplication and non-patent publications referred to in thisspecification and/or listed in the Application Data Sheet areincorporated herein by reference, in their entirety. Aspects of theembodiments can be modified, if necessary to employ concepts of thevarious patents, application and publications to provide yet furtherembodiments.

These and other changes can be made to the embodiments in light of theabove-detailed description. In general, in the following claims, theterms used should not be construed to limit the claims to the specificembodiments disclosed in the specification and the claims, but should beconstrued to include all possible embodiments along with the full scopeof equivalents to which such claims are entitled. Accordingly, theclaims are not limited by the disclosure.

1-112. (canceled)
 113. A wound closure device comprising: a basecomprising: a first exterior portion; a second exterior portion; amiddle portion connecting the first exterior portion and the secondexterior portion; and a first planar surface extending from the firstexterior portion, across the middle portion and to the second exteriorportion; a first microstructure attached to and extending from the firstplanar surface at the first end; and a second microstructure attached toand extending from the first planar surface at the second end.
 114. Thewound closure device of claim 113, wherein the first microstructure andthe second microstructure each comprises a single microstaple or twomicrostaples.
 115. The wound closure device of claim 114, wherein thefirst microstructure and the second microstructure each comprises morethan two microstaples.
 116. The wound closure device of claim 113,wherein the microstructure comprises a microstaple, microneedle,microblade, microanchor, microfishscale, micropillar, or microhair. 117.The wound closure device of claim 113, wherein: the wound closure deviceextends along a longitudinal axis; the first exterior portion and thesecond exterior portion define widths relative to the longitudinal axisthat are equal; and the middle portion comprises an isthmus having awidth smaller than those of the first exterior portion and the secondexterior portion.
 118. The wound closure device of claim 117, whereinthe first exterior portion and the second exterior portion arestretchable and the isthmus is non-stretchable.
 119. The wound closuredevice of claim 113, further comprising a backing positioned adjacent tothe base, wherein the backing is in the form of a roll.
 120. The woundclosure device of claim 113, wherein the base is in the form of a rollcomprising a plurality of microstructure arrays.
 121. The wound closuredevice of claim 113, wherein the base is in the form of a rollcomprising one long array of microstructures extending along thelongitudinal axis.
 122. The wound closure device of claim 120, whereinthe base is in the form of a roll comprising a plurality of basesconnected end-to-end.
 123. The wound closure device of claim 120,further comprising a drug or therapeutic located on the isthmus. 124.The wound closure device of claim 120, further comprising an applicatordevice.
 125. The wound closure device of claim 124, wherein theapplicator comprises a handheld dispenser.
 126. The wound closure deviceof claim 125, wherein the handheld dispenser includes a means forseparating the roll or bandage.
 127. The wound closure device of claim126, wherein: the handheld dispenser comprises a roll-on dispenser; andthe means for separating comprises a blade that can be placed at anangle that allows for cutting of the roll or bandage upon an upwardrotation of a medical care provider's hand.
 128. The wound closuredevice of claim 120, wherein said microstructure arrays are separated bya non-stretchable isthmus, and in that said base is stretchable or saidmicrostructure arrays are attached to a stretchable backing.
 129. Awound closure device comprising two or more microstructure arrays upon abase, each microstructure array comprising one or more microstructures,characterized in that said microstructure arrays are separated by anon-stretchable isthmus, and in that said base is stretchable or saidmicrostructure arrays are attached to a stretchable backing.